Sphingomyelin Lipidosis
Conditions
Brief summary
Primary Objective: To evaluate the safety and tolerability of olipudase alfa administered intravenously in pediatric participants every 2 weeks for 64 weeks. Secondary Objective: To characterize the pharmacokinetic profile and evaluate the pharmacodynamics and exploratory efficacy of olipudase alfa administered intravenously in pediatric participants every 2 weeks for 64 weeks.
Detailed description
The maximum study duration per participant was approximately 18 months (screening period: up to 60 days; treatment period: 64 weeks; post-treatment period: up to 37 days, not applicable if participants enrolled in a long-term extension treatment trial).
Interventions
DRUGOlipudase alfa
Pharmaceutical form: powder for concentrate for solution for infusion Route of administration: intravenous infusion
Sponsors
Genzyme, a Sanofi Company
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 17 Years
Healthy volunteers
No
Inclusion criteria
: * The participant and/or participant's parent(s)/legal guardian(s) must provide written informed assent/consent prior to any protocol-related procedures being performed. * The participant was \<18 years of age on the date of informed assent/consent. * The participant had documented deficiency of acid sphingomyelinase as measured in peripheral leukocytes, cultured fibroblasts, or lymphocytes. * The participant had a spleen volume greater than or equal to (\>=) 5 multiples of normal (MN) measured by magnetic resonance imaging (MRI); participants who had partial splenectomy were allowed if the procedure was performed \>=1 year before screening and the residual spleen volume was \>=5 MN. * The participant's height was -1 Z-score or lower. * A negative serum pregnancy test in female participants of childbearing potential. * Female participants of childbearing potential and male participants must be willing to practice true abstinence in line with their preferred and usual lifestyle or use 2 acceptable effective methods of contraception.
Exclusion criteria
* The participant had received an investigational drug within 30 days before study enrollment. * The participant had any of the following medical conditions: * An active, serious, intercurrent illness. * Active hepatitis B or hepatitis C infection. * Infection with human immunodeficiency virus (HIV). * Cirrhosis (determined by clinical evaluation). * Significant cardiac disease (eg, clinically significant arrhythmia, moderate or severe pulmonary hypertension or valvular dysfunction, or \<40 percent (%) left ventricular ejection fraction by echocardiogram). * Malignancy diagnosed within the previous 5 years (except basal cell carcinoma). * Any other extenuating circumstance that can significantly interfere with study compliance, including all prescribed evaluations and follow-up activities. * The participant had acute or rapidly progressive neurological abnormalities. * The participant was homozygous for SMPD1 gene mutations R496L, L302P, and fs330 or any combination of these 3 mutations. * The participant had a delay of gross motor skills. * The participant had a major organ transplant (eg, bone marrow, liver). * The participant required use of invasive ventilatory support. * The participant required use of noninvasive ventilatory support while awake and for greater than (\>)12 hours a day. * The participant in the investigator's opinion, was unable to adhere to the requirements of the study. * The participant had a platelet count \<60 × 10\^3/µL (based on the average of 2 screening samples obtained up to 24 hours apart). * The participant had alanine aminotransferase or aspartate aminotransferase \>250 IU/L or total bilirubin \>1.5 mg/dL. * The participant had an international normalized ratio (INR) \>1.5. * The participant was unwilling or unable to abstain from ingesting alcohol the day before through 3 days after each infusion of olipudase alfa during the treatment period. Measuring alcohol concentration in blood was not required. * The participant was scheduled during the study for in-patient hospitalization including elective surgery. * The participant required medication(s) that may can decrease olipudase alfa activity (eg, fluoxetine, chlorpromazine; tricyclic antidepressants \[eg, imipramine, or desipramine\]). * The participant was breast-feeding. The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Doppler Echocardiogram: Absolute Change From Baseline in Left Ventricular Ejection Fraction at Week 52 | Baseline, Week 52 (last assessment) | — |
| Change From Baseline in Safety Biomarker: Cardiac Troponin I and Ferritin at Week 64 | Baseline, Week 64 (pre-infusion) | — |
| Change From Baseline in Safety Biomarker: Interleukin (IL)-6 and IL-8 at Week 24 | Baseline, Week 24 (pre-infusion, last assessment) | — |
| Change From Baseline in Safety Biomarker: Calcitonin at Week 64 | Baseline, Week 64 (pre-infusion) | — |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | From Baseline up to End of study (64 weeks) | TEAEs were defined as adverse events (AEs) that occurred or worsened during the on-treatment period (time from the start of investigational medicinal product \[IMP\]) administration until end of study (i.e. up to 64 weeks). |
| Number of Participants With Infusion-Associated Reactions (IARs) | Within up to 24 hours after start of any infusion (during the treatment period i.e. from Baseline up to 64 weeks) | IARs were defined as AEs that occurred during the infusion or within up to 24 hours after the start of infusion and were considered as related or possibly related to the study treatment by the investigator or the sponsor. Protocol-defined IAR: all AEs that were identified as an IAR by the investigator. Events occurring greater than or equal to (\>=) 24 hours after the start of an infusion might had been judged an IAR at the discretion of the investigator or sponsor. |
| Number of Participants With Change in Physical Examination | Baseline, Week 52 (last complete assessment) | Change from Normal assessment (at Baseline) to Abnormal assessment (at Week 52) was reported. Physical examinations included following observations/measurements: examination of the skin, head, eyes, ears, nose, and throat; lymph nodes; heart, lungs, and abdomen; extremities and joints. Abnormality in physical examinations was based on investigator's discretion. |
| Number of Participants With Change in Neurological Examination | Baseline, Week 52 (last assessment) | Change from Normal assessment (at Baseline) to Abnormal assessment (at Week 52) was reported. Neurological examination included: coordination examination, cranial nerve examination, extrapyramidal features, fundoscopy, gait and coordination examination, motor examination, tone peripheral nervous system, reflexes examination, sensory examination, strength examination, mental status. |
| Number of Participants With Abnormal Liver Function Laboratory Values at the End of Study | At End of Study (Week 64) | Abnormal values in alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, and alkaline phosphatase were reported. |
| Number of Participants With Potentially Clinically Significant Vital Sign Abnormalities | From Baseline up to End of Study (64 weeks) | * Heart Rate (HR) High: \>=120 beats per minute (bpm) (adolescents), \>=120 bpm (children), \>=140 bpm (early children), \>=175 bpm (infants) & increase from baseline (IFB) \>=20 bpm for all age categories. * HR Low: \<=50 bpm (adolescents), \<=50 bpm (children), \<=75 bpm (early children), \<=80 bpm (infants) & decrease from baseline (DFB) \>=20 bpm for all age categories. * Systolic BP (SBP) High: \>=119 mmHg (adolescents), 108 mmHg (children), 101 mmHg (in early children), 98 mmHg (infants) & IFB \>=20 mmHg for all age categories. * SBP Low: \<=90 mmHg (adolescents), \<= 80mm Hg (children), \<=70 mmHg (early children), \<=70 mmHg (infants) & DFB \>=20 mmHg for all age categories. * Diastolic BP (DBP) High:\>=78 mmHg (adolescents), \>=72 mmHg (children), \>=59 mmHg (in early children), \>=54 mmHg (infants) & IFB \>=10 mmHg for all age categories. * DBP Low:\<=54 mmHg (adolescents), \<=48 mmHg (children), \<=34 mmHg (early children), \<=34 mmHg (infants) & DFB \>=10 mmHg for all age categories. |
| Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Abnormalities | From Baseline up to End of Study (64 weeks) | Criteria for potentially clinically significant ECG abnormalities: * High PR Interval: \>=180 milliseconds (ms) in adolescents, 170 ms in children, 160 ms in early children, and 140 ms in infants; * High QRS Interval: \>=110 ms in adolescents, 100 ms in children, 95 ms in early children and 85 ms in infants; * Prolonged QTc Fridericia (QTc F): \>450 ms in male adolescents, children, early children and infants or 470 ms in female adolescents, * QTc F \>500 ms; * QTc F increase from baseline \>60 ms. |
| Change From Baseline in Safety Biomarker Level: High Sensitivity C Reactive Protein (hsCRP) at Week 64 | Baseline, Week 64 (pre-infusion) | — |
| Change From Baseline in Safety Biomarker: Ceramide Level at Week 64 | Baseline, Week 64 (pre-infusion) | — |
| Change From Baseline in Safety Biomarker: Iron at Week 64 | Baseline, Week 64 (pre-infusion) | — |
| Number of Participants With Treatment-Emergent Antibody: Treatment-Induced/Treatment-Boosted Anti-drug Antibodies and Neutralizing Antibody (NAb) | From Baseline up to Week 64 | Serum samples for immunogenicity assessment were analyzed to detect ADA. ADA response were categorized as: treatment emergent antibody i.e. treatment-induced/treatment-boosted response. A participant whose ADA status was positive anytime post-baseline and was negative or missing at baseline was considered to have treatment induced ADA. A participant whose ADA status was positive at baseline (pre-existing ADA) and the ADA titer level anytime post-baseline was significantly higher than that at baseline is considered to have treatment boosted ADA. Positive samples in the ADA assay were further analyzed in the NAb assay as positive NAb inhibition of catalytic activity and positive NAb inhibition of cellular uptake. |
| Number of Participants With Abnormalities in Liver Ultrasound Doppler at Week 52 | Week 52 (last assessment) | Evidence of portal hypertension was assessed by portal vein direction from liver ultrasound doppler. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Bone Biomarkers at Week 52 | Baseline, Week 52 | Bone biomarkers included bone specific alkaline phosphatase, C-Telopeptide. |
| Pharmacokinetic (PK) Parameter: Plasma Concentration of Olipudase Alfa at the End of Infusion (Ceoi) | At the end of infusion of the first 3.0 mg/kg dose and at Week 52 | Ceoi was defined as the plasma concentration at the end of infusion (EOI). Data collected for child and Infant/child age groups at 0-30 min from end of infusion was considered at end of infusion. |
| Percent Change From Baseline in Pharmacodynamic Biomarkers: Plasma Sphingomyelin and Lyso-Sphingomyelin Levels at Week 52 | Baseline, Week 52 (Pre- infusion) | Sphingomyelin and Lyso-sphingomyelin levels were assessed in plasma. Lyso-sphingomyelin is a metabolite of sphingomyelin. |
| Change From Baseline in Health Outcome Questionnaires : Pediatric Quality of Life (PedsQL) Generic Core Total Scale Scores at Week 52 | Baseline, Week 52 (last assessment) | PedsQL includes a child self-report (CS-R) for participants 5 to 18 years and parents' report (PR) of participants 2 to 18 years. CS-R: 23-item PedsQL Generic Core Scales report includes 4 scales, Physical (P), Emotional (E), Social (S), and School Functioning (SF). PR: 21-item PedsQL Generic Core Scales report includes P, E, S, and SF scales. Each item used a 5-point rating scale ( from 0=never to 4=almost always). Items are reverse scored and linearly transformed to a 0 (almost always) -100 (never) scale. Higher score indicates better Health Related Quality of Life (HRQoL). P, E, S and SF summary scores are calculated as mean of respective functioning items. Psychosocial Health Summary Score is calculated as mean of 13 or 15 items (E, S and SF). Generic core total scale score is calculated as the mean of all the 21 or 23 items (P, E, S and SF). All summary/total scores are mean of specific items and they all have values ranges from 0 to 100, where higher score=better HRQoL. |
| Pharmacokinetic Parameter: Maximum Observed Plasma Concentration (Cmax) of Olipudase Alfa | Adolescent: at pre-infusion, EOI, 2 h, 6 h, 24 h, 48 h & 72 h (at first 3.0 mg/kg dose) or 96 h (at Week 52) post EOI; Child & infant/early child: pre-infusion, 0-30 min, 2-4 h, 6-12 h, 24-36 h, and 84-96 h post EOI at the first 3.0 mg/kg dose & Week 52 | Cmax: maximum plasma concentration observed. |
| Pharmacokinetic Parameter: AUC0-last, AUC(0-tau) of Olipudase Alfa | Adolescent: at pre-infusion, EOI, 2 h, 6 h, 24 h, 48 h & 72 h (at first 3.0 mg/kg dose) or 96 h (at Week 52) post EOI; Child & infant/early child: pre-infusion, 0-30 min, 2-4 h, 6-12 h, 24-36 h, and 84-96 h post EOI at the first 3.0 mg/kg dose & Week 52 | AUClast: Area under the plasma concentration versus time curve calculated using the trapezoidal method from time zero to the time of last measured concentration. AUC(0-tau): area under the plot of the drug concentration versus the time curve from time 0 to the end of the dosing interval (tau), where dosing interval was 2 weeks. |
| Pharmacokinetic Parameter: Terminal Half-Life of Olipudase Alfa | Adolescent: at pre-infusion, EOI, 2 h, 6 h, 24 h, 48 h & 72 h (at first 3.0 mg/kg dose) or 96 h (at Week 52) post EOI; Child & infant/early child: pre-infusion, 0-30 min, 2-4 h, 6-12 h, 24-36 h, and 84-96 h post EOI at the first 3.0 mg/kg dose & Week 52 | Half-life is the time measured for the plasma concentration of drug to decrease by one half. |
| Pharmacokinetic Parameter: Total Body Clearance (CL) of Olipudase Alfa | Adolescent: at pre-infusion, EOI, 2 h, 6 h, 24 h, 48 h & 72 h (at first 3.0 mg/kg dose) or 96 h (at Week 52) post EOI; Child & infant/early child: pre-infusion, 0-30 min, 2-4 h, 6-12 h, 24-36 h, and 84-96 h post EOI at the first 3.0 mg/kg dose & Week 52 | Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. Total body clearance of a drug from the plasma calculated using equations below: CL = Dose / AUC after the first dose. |
| Pharmacokinetic Parameter: Volume of Distribution at Steady State (Vss) of Olipudase Alfa | Adolescent: at pre-infusion, EOI, 2 h, 6 h, 24 h, 48 h & 72 h (at first 3.0 mg/kg dose) or 96 h (at Week 52) post EOI; Child & infant/early child: pre-infusion, 0-30 min, 2-4 h, 6-12 h, 24-36 h, and 84-96 h post EOI at the first 3.0 mg/kg dose & Week 52 | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. |
| Pharmacokinetic Parameter: Time to Reach Cmax (Tmax) of Olipudase Alfa | Adolescent: at pre-infusion, EOI, 2 h, 6 h, 24 h, 48 h & 72 h (at first 3.0 mg/kg dose) or 96 h (at Week 52) post EOI; Child & infant/early child: pre-infusion, 0-30 min, 2-4 h, 6-12 h, 24-36 h, and 84-96 h post EOI at the first 3.0 mg/kg dose & Week 52 | tmax: time to reach maximum plasma concentration observed. |
| Percent Change From Baseline in Spleen Volume and Liver Volume at Week 52 | Baseline, Week 52 (last assessment) | Spleen and liver volumes was assessed by abdominal magnetic resonance imaging (MRI). |
| Change From Baseline in Interstitial Lung Disease Score Measured Using High Resolution Computed Tomography (HRCT) at Week 52 For Both Lungs | Baseline, Week 52 (last assessment) | Pulmonary imaging of chest using HRCT was obtained to quantitate the degree of possible infiltrative lung disease. Lung fields were assessed by a central reader & scored subjectively for the degree of interstitial lung disease on a scale ranges from 0 =normal, 1 =mild, 2=moderate and 3 =severe, where higher scores indicate more severity. |
| Change From Baseline in Height Z-Scores at Week 52 | Baseline, Week 52 (last assessment) | Z-score for height of participants was evaluated. Height Z-Score, i.e., the height-for-age Z Score, is the number of standard deviations of the actual height of a child from the median height of the children of the corresponding age and sex as determined from the standard sample. A height Z-score of 0 is equal to the median and is considered normal. Negative numbers indicate values lower than the median and positive numbers indicate values higher than the median. For analysis, mean Z-score was calculated and an increase of mean height Z-score from baseline indicates an improvement on growth. |
| Percent Change From Baseline in Percent Predicted Hemoglobin-Adjusted Diffusing Capacity of Carbon Monoxide (DLco) at Week 52 | Baseline, Week 52 (last assessment) | Percent predicted Hemoglobin-adjusted DLco was calculated as: 100\*Adjusted DLco/Predicted DLco in unit of mL CO/min/mmHg where, adjusted DLco = Observed DLco (in mL CO/min/mmHg) divided by Hemoglobin-adjusted factor. Per planned analysis, pulmonary function testing (PFT) was to be performed only on participants \>=5 years of age therefore, data for participants in age cohort: infant/early child were not collected. |
| Change From Baseline in Difference Between Actual Age and Bone Age of Participants at Week 52 | Baseline, Week 52 (last assessment) | Hand X-ray was performed on participant's left hand, fingers and wrist to assess bone age of participants. At each visit (Baseline and Week 52), difference between the bone age and actual age at that visit was calculated. Difference in age in months was calculated as bone age in months minus real age at time of assessment (in months) at specified time points. In this outcome measure change from baseline at Week 52 in the difference between actual age and bone age (in months) is reported. |
| Change From Baseline in Cycle Ergometry: Maximum Workload at Week 52 | Baseline, Week 52 (last assessment) | Cardiopulmonary status was assessed using a stationary one-wheeled cycle used as an ergometer to measure a person's work output under controlled conditions. Participants were asked to ride the cycle at increasing workload levels until they could no longer proceed. The workload at which participant stopped and cannot proceed was considered as maximum workload (in watt). As per the planned analysis, this assessment was not to be performed on participants that were \<=6 years of age or \<120 cm in height on day 1/week 0, therefore infant/early child cohort was not evaluable. |
| Physician's Global Assessment of Participant's Progress: Observed Scores at Week 52 | Week 52 (last assessment) | Physician assessed participant's current clinical status (refers to clinical status at Week 52 in comparison to Baseline) was evaluated by marking 1 of the following 7 categories: • marked improvement, • moderate improvement, • mild improvement, • no change, • mild worsening, • moderate worsening, or • marked worsening. These 7 categories were converted to scores as follows: 3 = marked improvement of daily activities, 2 = moderate improvement of daily activities, 1 = mild improvement of daily activities, 0 = no change, -1 = mild worsening of daily activities, -2 = moderate worsening of daily activities, -3 = marked worsening of daily activities where higher score indicated improvement in daily activities as compared to baseline. In this outcome measure, observed scores of participant's clinical status at Week 52 are reported. |
| Percent Change From Baseline in Efficacy Biomarkers Level at Week 52 | Baseline, Week 52 | Efficacy biomarkers included chitotriosidase, chemokine ligand 18 (CCL18), angiotensin-converting enzyme (ACE). |
| Percent Change From Baseline in Lipid Profile at Week 52 | Baseline, Week 52 | Lipid profile parameters included low density lipoprotein (LDL)-cholesterol, high density lipoprotein (HDL)-cholesterol and triglycerides. |
Countries
Brazil, France, Germany, Italy, United Kingdom, United States
Participant flow
Recruitment details
The study was conducted at 6 sites in 6 countries between 01 May 2015 and 09 December 2019.
Pre-assignment details
A total of 23 participants were screened out of which 20 participants were included and treated in this study.
Participants by arm
| Arm | Count |
|---|---|
| Olipudase Alfa: Adolescent Cohort Participants aged 12 to \< 18 years received IV infusion of olipudase alfa Q2W for 64 weeks. Each participant underwent a dose escalation according to the following paradigm: 0.03, 0.1, 0.3, 0.3, 0.6, 0.6, 1.0, 2.0 , 3.0 mg/kg. Three (3) mg/kg was the target maintenance dose, which was maintained for the remaining duration of 64 treatment weeks. | 4 |
| Olipudase Alfa: Child Cohort Participants aged 6 to \<12 years received IV infusion of olipudase alfa Q2W for 64 weeks. Each participant underwent a dose escalation according to the following paradigm: 0.03, 0.1, 0.3, 0.3, 0.6, 0.6, 1.0, 2.0, 3.0 mg/kg. Three (3) mg/kg was the target maintenance dose, which was maintained for the remaining duration of 64 treatment weeks. | 9 |
| Olipudase Alfa: Infant/Early Child Cohort Participants aged \<6 years received IV infusion of olipudase alfa Q2W for 64 weeks. Each participant underwent a dose escalation according to the following paradigm: 0.03, 0.1, 0.3, 0.3, 0.6, 0.6, 1.0, 2.0, 3.0 mg/kg. Three (3) mg/kg was the target maintenance dose, which was maintained for the remaining duration of 64 treatment weeks. | 7 |
| Total | 20 |
Baseline characteristics
| Characteristic | Olipudase Alfa: Child Cohort | Total | Olipudase Alfa: Adolescent Cohort | Olipudase Alfa: Infant/Early Child Cohort |
|---|---|---|---|---|
| Age, Continuous | 8.69 years STANDARD_DEVIATION 1.69 | 8.20 years STANDARD_DEVIATION 4.39 | 14.84 years STANDARD_DEVIATION 2.22 | 3.77 years STANDARD_DEVIATION 1.44 |
| High Sensitivity C Reactive Protein (hsCRP) Level in Plasma | 0.410 milligrams per liter (mg/L) STANDARD_DEVIATION 0.337 | 0.704 milligrams per liter (mg/L) STANDARD_DEVIATION 1.041 | 1.863 milligrams per liter (mg/L) STANDARD_DEVIATION 1.855 | 0.306 milligrams per liter (mg/L) STANDARD_DEVIATION 0.249 |
| Percent Left Ventricular Ejection Fraction | 64.25 percent ejection fraction STANDARD_DEVIATION 6.27 | 65.11 percent ejection fraction STANDARD_DEVIATION 6.72 | 60.50 percent ejection fraction STANDARD_DEVIATION 4.04 | 68.71 percent ejection fraction STANDARD_DEVIATION 7.16 |
| Pharmacodynamic Biomarker: Lyso-Sphingomyelin in Plasma | 653.667 ug/L STANDARD_DEVIATION 226.301 | 626.300 ug/L STANDARD_DEVIATION 276.528 | 488.250 ug/L STANDARD_DEVIATION 153.489 | 670.000 ug/L STANDARD_DEVIATION 382.137 |
| Pharmacodynamic Biomarker: Sphingomyelin in Plasma | 430.8 mg/L STANDARD_DEVIATION 191.3 | 375.1 mg/L STANDARD_DEVIATION 137.3 | 348.3 mg/L STANDARD_DEVIATION 27.5 | 318.7 mg/L STANDARD_DEVIATION 41 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Black | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Northeast Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Not reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Southeast Asian | 1 Participants | 2 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Unknown | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 7 Participants | 17 Participants | 3 Participants | 7 Participants |
| Safety Biomarker: Calcitonin Level in Plasma | 9.031 ng/L STANDARD_DEVIATION 8.601 | 10.146 ng/L STANDARD_DEVIATION 9.137 | 7.675 ng/L STANDARD_DEVIATION 13.33 | 12.991 ng/L STANDARD_DEVIATION 7.843 |
| Safety Biomarker: Cardiac Troponin I Level in Plasma | 0.020 micrograms per liter (μg/L) STANDARD_DEVIATION 0 | 0.020 micrograms per liter (μg/L) STANDARD_DEVIATION 0 | 0.020 micrograms per liter (μg/L) STANDARD_DEVIATION 0 | 0.020 micrograms per liter (μg/L) STANDARD_DEVIATION 0 |
| Safety Biomarker: Ceramide Level in Plasma | 5.57 mg/L STANDARD_DEVIATION 1.87 | 6.74 mg/L STANDARD_DEVIATION 3.51 | 7.13 mg/L STANDARD_DEVIATION 2.14 | 8.01 mg/L STANDARD_DEVIATION 5.3 |
| Safety Biomarker: Ferritin Level in Plasma | 68.700 μg/L STANDARD_DEVIATION 36.733 | 60.285 μg/L STANDARD_DEVIATION 31.173 | 65.775 μg/L STANDARD_DEVIATION 21.088 | 46.329 μg/L STANDARD_DEVIATION 26.5 |
| Safety Biomarker: IL-8 Level in Plasma | 35.72 ng/L STANDARD_DEVIATION 29.15 | 32.35 ng/L STANDARD_DEVIATION 25.43 | 24.75 ng/L STANDARD_DEVIATION 14.5 | — |
| Safety Biomarker: Interleukin (IL)-6 Level in Plasma | 11.15 nanogram/liter (ng/L) STANDARD_DEVIATION 25.62 | 8.73 nanogram/liter (ng/L) STANDARD_DEVIATION 21.84 | 2.27 nanogram/liter (ng/L) STANDARD_DEVIATION 0.87 | — |
| Safety Biomarker: Iron Level in Plasma | 10.96 micromole/liter (umol/L) STANDARD_DEVIATION 2.31 | 10.09 micromole/liter (umol/L) STANDARD_DEVIATION 2.32 | 10.13 micromole/liter (umol/L) STANDARD_DEVIATION 2.38 | 8.52 micromole/liter (umol/L) STANDARD_DEVIATION 1.81 |
| Sex: Female, Male Female | 5 Participants | 10 Participants | 1 Participants | 4 Participants |
| Sex: Female, Male Male | 4 Participants | 10 Participants | 3 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 9 | 0 / 7 | 0 / 20 |
| other Total, other adverse events | 4 / 4 | 9 / 9 | 7 / 7 | 20 / 20 |
| serious Total, serious adverse events | 0 / 4 | 1 / 9 | 4 / 7 | 5 / 20 |
Outcome results
Primary
Change From Baseline in Safety Biomarker: Calcitonin at Week 64
Time frame: Baseline, Week 64 (pre-infusion)
Population: Analysis was performed on safety population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Olipudase Alfa: Adolescent Cohort | Change From Baseline in Safety Biomarker: Calcitonin at Week 64 | 3.612 ng/L | Standard Deviation 7.225 |
| Olipudase Alfa: Child Cohort | Change From Baseline in Safety Biomarker: Calcitonin at Week 64 | -5.337 ng/L | Standard Deviation 3.962 |
| Olipudase Alfa: Infant/Early Child Cohort | Change From Baseline in Safety Biomarker: Calcitonin at Week 64 | -8.609 ng/L | Standard Deviation 6.359 |
| Total Participants | Change From Baseline in Safety Biomarker: Calcitonin at Week 64 | -4.710 ng/L | Standard Deviation 6.929 |
Primary
Change From Baseline in Safety Biomarker: Cardiac Troponin I and Ferritin at Week 64
Time frame: Baseline, Week 64 (pre-infusion)
Population: Analysis was performed on safety population. Here 'number analyzed' = participants with available data for specified categories.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Olipudase Alfa: Adolescent Cohort | Change From Baseline in Safety Biomarker: Cardiac Troponin I and Ferritin at Week 64 | Troponin: Pre-infusion: Week 64 | 0.000 μg/L | Standard Deviation 0 |
| Olipudase Alfa: Adolescent Cohort | Change From Baseline in Safety Biomarker: Cardiac Troponin I and Ferritin at Week 64 | Ferritin: Pre-infusion: Week 64 | -38.325 μg/L | Standard Deviation 16.438 |
| Olipudase Alfa: Child Cohort | Change From Baseline in Safety Biomarker: Cardiac Troponin I and Ferritin at Week 64 | Ferritin: Pre-infusion: Week 64 | -45.611 μg/L | Standard Deviation 32.963 |
| Olipudase Alfa: Child Cohort | Change From Baseline in Safety Biomarker: Cardiac Troponin I and Ferritin at Week 64 | Troponin: Pre-infusion: Week 64 | 0.000 μg/L | Standard Deviation 0 |
| Olipudase Alfa: Infant/Early Child Cohort | Change From Baseline in Safety Biomarker: Cardiac Troponin I and Ferritin at Week 64 | Ferritin: Pre-infusion: Week 64 | -28.186 μg/L | Standard Deviation 19.793 |
| Olipudase Alfa: Infant/Early Child Cohort | Change From Baseline in Safety Biomarker: Cardiac Troponin I and Ferritin at Week 64 | Troponin: Pre-infusion: Week 64 | 0.000 μg/L | Standard Deviation 0 |
| Total Participants | Change From Baseline in Safety Biomarker: Cardiac Troponin I and Ferritin at Week 64 | Troponin: Pre-infusion: Week 64 | 0.000 μg/L | Standard Deviation 0 |
| Total Participants | Change From Baseline in Safety Biomarker: Cardiac Troponin I and Ferritin at Week 64 | Ferritin: Pre-infusion: Week 64 | -38.055 μg/L | Standard Deviation 26.207 |
Primary
Change From Baseline in Safety Biomarker: Ceramide Level at Week 64
Time frame: Baseline, Week 64 (pre-infusion)
Population: Analysis was performed on safety population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Olipudase Alfa: Adolescent Cohort | Change From Baseline in Safety Biomarker: Ceramide Level at Week 64 | -3.90 mg/L | Standard Deviation 2.41 |
| Olipudase Alfa: Child Cohort | Change From Baseline in Safety Biomarker: Ceramide Level at Week 64 | -3.23 mg/L | Standard Deviation 2.17 |
| Olipudase Alfa: Infant/Early Child Cohort | Change From Baseline in Safety Biomarker: Ceramide Level at Week 64 | -5.93 mg/L | Standard Deviation 4.91 |
| Total Participants | Change From Baseline in Safety Biomarker: Ceramide Level at Week 64 | -4.31 mg/L | Standard Deviation 3.48 |
Primary
Change From Baseline in Safety Biomarker: Interleukin (IL)-6 and IL-8 at Week 24
Time frame: Baseline, Week 24 (pre-infusion, last assessment)
Population: Analysis was performed on safety population. Here 'number analyzed'=participants with available data for specified categories. Data was not planned to be collected and reported for the Infant/Early Child Cohort, per protocol.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Olipudase Alfa: Adolescent Cohort | Change From Baseline in Safety Biomarker: Interleukin (IL)-6 and IL-8 at Week 24 | IL-6 | 0.47 ng/L | Standard Deviation 3.23 |
| Olipudase Alfa: Adolescent Cohort | Change From Baseline in Safety Biomarker: Interleukin (IL)-6 and IL-8 at Week 24 | IL-8 | -7.25 ng/L | Standard Deviation 14.5 |
| Olipudase Alfa: Child Cohort | Change From Baseline in Safety Biomarker: Interleukin (IL)-6 and IL-8 at Week 24 | IL-6 | 0.89 ng/L | Standard Deviation 5.66 |
| Olipudase Alfa: Child Cohort | Change From Baseline in Safety Biomarker: Interleukin (IL)-6 and IL-8 at Week 24 | IL-8 | -18.22 ng/L | Standard Deviation 29.15 |
| Olipudase Alfa: Infant/Early Child Cohort | Change From Baseline in Safety Biomarker: Interleukin (IL)-6 and IL-8 at Week 24 | IL-6 | 0.77 ng/L | Standard Deviation 4.95 |
| Olipudase Alfa: Infant/Early Child Cohort | Change From Baseline in Safety Biomarker: Interleukin (IL)-6 and IL-8 at Week 24 | IL-8 | -14.85 ng/L | Standard Deviation 25.43 |
Primary
Change From Baseline in Safety Biomarker: Iron at Week 64
Time frame: Baseline, Week 64 (pre-infusion)
Population: Analysis was performed on safety population. Here, overall number of participants analyzed = participants with available data for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Olipudase Alfa: Adolescent Cohort | Change From Baseline in Safety Biomarker: Iron at Week 64 | 1.40 umol/L | Standard Deviation 3.53 |
| Olipudase Alfa: Child Cohort | Change From Baseline in Safety Biomarker: Iron at Week 64 | -0.41 umol/L | Standard Deviation 5.07 |
| Olipudase Alfa: Infant/Early Child Cohort | Change From Baseline in Safety Biomarker: Iron at Week 64 | 1.52 umol/L | Standard Deviation 4.31 |
| Total Participants | Change From Baseline in Safety Biomarker: Iron at Week 64 | 0.58 umol/L | Standard Deviation 4.38 |
Primary
Change From Baseline in Safety Biomarker Level: High Sensitivity C Reactive Protein (hsCRP) at Week 64
Time frame: Baseline, Week 64 (pre-infusion)
Population: Analysis was performed on safety population. Here, overall number of participants analyzed = participants with available data for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Olipudase Alfa: Adolescent Cohort | Change From Baseline in Safety Biomarker Level: High Sensitivity C Reactive Protein (hsCRP) at Week 64 | -1.603 mg/L | Standard Deviation 1.976 |
| Olipudase Alfa: Child Cohort | Change From Baseline in Safety Biomarker Level: High Sensitivity C Reactive Protein (hsCRP) at Week 64 | -0.168 mg/L | Standard Deviation 0.411 |
| Olipudase Alfa: Infant/Early Child Cohort | Change From Baseline in Safety Biomarker Level: High Sensitivity C Reactive Protein (hsCRP) at Week 64 | -0.206 mg/L | Standard Deviation 0.249 |
| Total Participants | Change From Baseline in Safety Biomarker Level: High Sensitivity C Reactive Protein (hsCRP) at Week 64 | -0.497 mg/L | Standard Deviation 1.074 |
Primary
Doppler Echocardiogram: Absolute Change From Baseline in Left Ventricular Ejection Fraction at Week 52
Time frame: Baseline, Week 52 (last assessment)
Population: Analysis was performed on safety population. Here, 'overall number of participants analyzed' = participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Olipudase Alfa: Adolescent Cohort | Doppler Echocardiogram: Absolute Change From Baseline in Left Ventricular Ejection Fraction at Week 52 | 0.33 percent ejection fraction | Standard Deviation 4.51 |
| Olipudase Alfa: Child Cohort | Doppler Echocardiogram: Absolute Change From Baseline in Left Ventricular Ejection Fraction at Week 52 | -1.00 percent ejection fraction | Standard Deviation 5.16 |
| Olipudase Alfa: Infant/Early Child Cohort | Doppler Echocardiogram: Absolute Change From Baseline in Left Ventricular Ejection Fraction at Week 52 | 1.17 percent ejection fraction | Standard Deviation 4.83 |
| Total Participants | Doppler Echocardiogram: Absolute Change From Baseline in Left Ventricular Ejection Fraction at Week 52 | 0.06 percent ejection fraction | Standard Deviation 4.71 |
Primary
Number of Participants With Abnormalities in Liver Ultrasound Doppler at Week 52
Evidence of portal hypertension was assessed by portal vein direction from liver ultrasound doppler.
Time frame: Week 52 (last assessment)
Population: Analysis was performed on safety population.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Olipudase Alfa: Adolescent Cohort | Number of Participants With Abnormalities in Liver Ultrasound Doppler at Week 52 | 0 Participants |
| Olipudase Alfa: Child Cohort | Number of Participants With Abnormalities in Liver Ultrasound Doppler at Week 52 | 0 Participants |
| Olipudase Alfa: Infant/Early Child Cohort | Number of Participants With Abnormalities in Liver Ultrasound Doppler at Week 52 | 0 Participants |
| Total Participants | Number of Participants With Abnormalities in Liver Ultrasound Doppler at Week 52 | 0 Participants |
Primary
Number of Participants With Abnormal Liver Function Laboratory Values at the End of Study
Abnormal values in alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, and alkaline phosphatase were reported.
Time frame: At End of Study (Week 64)
Population: Analysis was performed on safety population. One participant may be counted in multiple categories.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Olipudase Alfa: Adolescent Cohort | Number of Participants With Abnormal Liver Function Laboratory Values at the End of Study | ALT | 0 Participants |
| Olipudase Alfa: Adolescent Cohort | Number of Participants With Abnormal Liver Function Laboratory Values at the End of Study | AST | 0 Participants |
| Olipudase Alfa: Adolescent Cohort | Number of Participants With Abnormal Liver Function Laboratory Values at the End of Study | Total Bilirubin | 0 Participants |
| Olipudase Alfa: Adolescent Cohort | Number of Participants With Abnormal Liver Function Laboratory Values at the End of Study | Alkaline Phosphatase | 2 Participants |
| Olipudase Alfa: Child Cohort | Number of Participants With Abnormal Liver Function Laboratory Values at the End of Study | AST | 1 Participants |
| Olipudase Alfa: Child Cohort | Number of Participants With Abnormal Liver Function Laboratory Values at the End of Study | Total Bilirubin | 0 Participants |
| Olipudase Alfa: Child Cohort | Number of Participants With Abnormal Liver Function Laboratory Values at the End of Study | Alkaline Phosphatase | 2 Participants |
| Olipudase Alfa: Child Cohort | Number of Participants With Abnormal Liver Function Laboratory Values at the End of Study | ALT | 1 Participants |
| Olipudase Alfa: Infant/Early Child Cohort | Number of Participants With Abnormal Liver Function Laboratory Values at the End of Study | Total Bilirubin | 0 Participants |
| Olipudase Alfa: Infant/Early Child Cohort | Number of Participants With Abnormal Liver Function Laboratory Values at the End of Study | AST | 0 Participants |
| Olipudase Alfa: Infant/Early Child Cohort | Number of Participants With Abnormal Liver Function Laboratory Values at the End of Study | Alkaline Phosphatase | 0 Participants |
| Olipudase Alfa: Infant/Early Child Cohort | Number of Participants With Abnormal Liver Function Laboratory Values at the End of Study | ALT | 1 Participants |
| Total Participants | Number of Participants With Abnormal Liver Function Laboratory Values at the End of Study | Alkaline Phosphatase | 4 Participants |
| Total Participants | Number of Participants With Abnormal Liver Function Laboratory Values at the End of Study | AST | 1 Participants |
| Total Participants | Number of Participants With Abnormal Liver Function Laboratory Values at the End of Study | ALT | 2 Participants |
| Total Participants | Number of Participants With Abnormal Liver Function Laboratory Values at the End of Study | Total Bilirubin | 0 Participants |
Primary
Number of Participants With Change in Neurological Examination
Change from Normal assessment (at Baseline) to Abnormal assessment (at Week 52) was reported. Neurological examination included: coordination examination, cranial nerve examination, extrapyramidal features, fundoscopy, gait and coordination examination, motor examination, tone peripheral nervous system, reflexes examination, sensory examination, strength examination, mental status.
Time frame: Baseline, Week 52 (last assessment)
Population: Analysis was performed on safety population. One participant may be counted in multiple categories.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Olipudase Alfa: Adolescent Cohort | Number of Participants With Change in Neurological Examination | Motor Examination, Tone | 0 Participants |
| Olipudase Alfa: Adolescent Cohort | Number of Participants With Change in Neurological Examination | Fundoscopy | 0 Participants |
| Olipudase Alfa: Adolescent Cohort | Number of Participants With Change in Neurological Examination | Strength Examination | 0 Participants |
| Olipudase Alfa: Adolescent Cohort | Number of Participants With Change in Neurological Examination | Sensory Examination | 0 Participants |
| Olipudase Alfa: Adolescent Cohort | Number of Participants With Change in Neurological Examination | Coordination Examination | 0 Participants |
| Olipudase Alfa: Adolescent Cohort | Number of Participants With Change in Neurological Examination | Reflexes Examination | 0 Participants |
| Olipudase Alfa: Adolescent Cohort | Number of Participants With Change in Neurological Examination | Extrapyramidal Features | 0 Participants |
| Olipudase Alfa: Adolescent Cohort | Number of Participants With Change in Neurological Examination | Gait and Coordination Examination | 0 Participants |
| Olipudase Alfa: Adolescent Cohort | Number of Participants With Change in Neurological Examination | Peripheral Nervous System | 0 Participants |
| Olipudase Alfa: Adolescent Cohort | Number of Participants With Change in Neurological Examination | Cranial Nerve Examination | 0 Participants |
| Olipudase Alfa: Adolescent Cohort | Number of Participants With Change in Neurological Examination | Mental Status | 0 Participants |
| Olipudase Alfa: Child Cohort | Number of Participants With Change in Neurological Examination | Extrapyramidal Features | 0 Participants |
| Olipudase Alfa: Child Cohort | Number of Participants With Change in Neurological Examination | Peripheral Nervous System | 0 Participants |
| Olipudase Alfa: Child Cohort | Number of Participants With Change in Neurological Examination | Gait and Coordination Examination | 0 Participants |
| Olipudase Alfa: Child Cohort | Number of Participants With Change in Neurological Examination | Motor Examination, Tone | 0 Participants |
| Olipudase Alfa: Child Cohort | Number of Participants With Change in Neurological Examination | Reflexes Examination | 0 Participants |
| Olipudase Alfa: Child Cohort | Number of Participants With Change in Neurological Examination | Sensory Examination | 0 Participants |
| Olipudase Alfa: Child Cohort | Number of Participants With Change in Neurological Examination | Strength Examination | 0 Participants |
| Olipudase Alfa: Child Cohort | Number of Participants With Change in Neurological Examination | Mental Status | 0 Participants |
| Olipudase Alfa: Child Cohort | Number of Participants With Change in Neurological Examination | Coordination Examination | 0 Participants |
| Olipudase Alfa: Child Cohort | Number of Participants With Change in Neurological Examination | Cranial Nerve Examination | 0 Participants |
| Olipudase Alfa: Child Cohort | Number of Participants With Change in Neurological Examination | Fundoscopy | 0 Participants |
| Olipudase Alfa: Infant/Early Child Cohort | Number of Participants With Change in Neurological Examination | Motor Examination, Tone | 0 Participants |
| Olipudase Alfa: Infant/Early Child Cohort | Number of Participants With Change in Neurological Examination | Extrapyramidal Features | 0 Participants |
| Olipudase Alfa: Infant/Early Child Cohort | Number of Participants With Change in Neurological Examination | Strength Examination | 1 Participants |
| Olipudase Alfa: Infant/Early Child Cohort | Number of Participants With Change in Neurological Examination | Mental Status | 0 Participants |
| Olipudase Alfa: Infant/Early Child Cohort | Number of Participants With Change in Neurological Examination | Coordination Examination | 0 Participants |
| Olipudase Alfa: Infant/Early Child Cohort | Number of Participants With Change in Neurological Examination | Gait and Coordination Examination | 0 Participants |
| Olipudase Alfa: Infant/Early Child Cohort | Number of Participants With Change in Neurological Examination | Fundoscopy | 1 Participants |
| Olipudase Alfa: Infant/Early Child Cohort | Number of Participants With Change in Neurological Examination | Cranial Nerve Examination | 0 Participants |
| Olipudase Alfa: Infant/Early Child Cohort | Number of Participants With Change in Neurological Examination | Reflexes Examination | 0 Participants |
| Olipudase Alfa: Infant/Early Child Cohort | Number of Participants With Change in Neurological Examination | Peripheral Nervous System | 0 Participants |
| Olipudase Alfa: Infant/Early Child Cohort | Number of Participants With Change in Neurological Examination | Sensory Examination | 0 Participants |
| Total Participants | Number of Participants With Change in Neurological Examination | Peripheral Nervous System | 0 Participants |
| Total Participants | Number of Participants With Change in Neurological Examination | Reflexes Examination | 0 Participants |
| Total Participants | Number of Participants With Change in Neurological Examination | Sensory Examination | 0 Participants |
| Total Participants | Number of Participants With Change in Neurological Examination | Strength Examination | 1 Participants |
| Total Participants | Number of Participants With Change in Neurological Examination | Gait and Coordination Examination | 0 Participants |
| Total Participants | Number of Participants With Change in Neurological Examination | Extrapyramidal Features | 0 Participants |
| Total Participants | Number of Participants With Change in Neurological Examination | Cranial Nerve Examination | 0 Participants |
| Total Participants | Number of Participants With Change in Neurological Examination | Mental Status | 0 Participants |
| Total Participants | Number of Participants With Change in Neurological Examination | Motor Examination, Tone | 0 Participants |
| Total Participants | Number of Participants With Change in Neurological Examination | Fundoscopy | 1 Participants |
| Total Participants | Number of Participants With Change in Neurological Examination | Coordination Examination | 0 Participants |
Primary
Number of Participants With Change in Physical Examination
Change from Normal assessment (at Baseline) to Abnormal assessment (at Week 52) was reported. Physical examinations included following observations/measurements: examination of the skin, head, eyes, ears, nose, and throat; lymph nodes; heart, lungs, and abdomen; extremities and joints. Abnormality in physical examinations was based on investigator's discretion.
Time frame: Baseline, Week 52 (last complete assessment)
Population: Analysis was performed on safety population. One participant may be counted in multiple categories.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Olipudase Alfa: Adolescent Cohort | Number of Participants With Change in Physical Examination | Lymph Nodes | 0 Participants |
| Olipudase Alfa: Adolescent Cohort | Number of Participants With Change in Physical Examination | General Appearance | 0 Participants |
| Olipudase Alfa: Adolescent Cohort | Number of Participants With Change in Physical Examination | Abdomen | 0 Participants |
| Olipudase Alfa: Adolescent Cohort | Number of Participants With Change in Physical Examination | Head, Eyes, Ears, Nose and Throat | 2 Participants |
| Olipudase Alfa: Adolescent Cohort | Number of Participants With Change in Physical Examination | Lungs | 0 Participants |
| Olipudase Alfa: Adolescent Cohort | Number of Participants With Change in Physical Examination | Heart | 0 Participants |
| Olipudase Alfa: Adolescent Cohort | Number of Participants With Change in Physical Examination | Extremities/Joints | 0 Participants |
| Olipudase Alfa: Adolescent Cohort | Number of Participants With Change in Physical Examination | Skin | 0 Participants |
| Olipudase Alfa: Child Cohort | Number of Participants With Change in Physical Examination | Lymph Nodes | 0 Participants |
| Olipudase Alfa: Child Cohort | Number of Participants With Change in Physical Examination | Lungs | 0 Participants |
| Olipudase Alfa: Child Cohort | Number of Participants With Change in Physical Examination | General Appearance | 1 Participants |
| Olipudase Alfa: Child Cohort | Number of Participants With Change in Physical Examination | Heart | 0 Participants |
| Olipudase Alfa: Child Cohort | Number of Participants With Change in Physical Examination | Head, Eyes, Ears, Nose and Throat | 0 Participants |
| Olipudase Alfa: Child Cohort | Number of Participants With Change in Physical Examination | Extremities/Joints | 1 Participants |
| Olipudase Alfa: Child Cohort | Number of Participants With Change in Physical Examination | Abdomen | 0 Participants |
| Olipudase Alfa: Child Cohort | Number of Participants With Change in Physical Examination | Skin | 1 Participants |
| Olipudase Alfa: Infant/Early Child Cohort | Number of Participants With Change in Physical Examination | Lungs | 0 Participants |
| Olipudase Alfa: Infant/Early Child Cohort | Number of Participants With Change in Physical Examination | Skin | 1 Participants |
| Olipudase Alfa: Infant/Early Child Cohort | Number of Participants With Change in Physical Examination | Abdomen | 0 Participants |
| Olipudase Alfa: Infant/Early Child Cohort | Number of Participants With Change in Physical Examination | Heart | 0 Participants |
| Olipudase Alfa: Infant/Early Child Cohort | Number of Participants With Change in Physical Examination | Extremities/Joints | 0 Participants |
| Olipudase Alfa: Infant/Early Child Cohort | Number of Participants With Change in Physical Examination | General Appearance | 1 Participants |
| Olipudase Alfa: Infant/Early Child Cohort | Number of Participants With Change in Physical Examination | Head, Eyes, Ears, Nose and Throat | 2 Participants |
| Olipudase Alfa: Infant/Early Child Cohort | Number of Participants With Change in Physical Examination | Lymph Nodes | 0 Participants |
| Total Participants | Number of Participants With Change in Physical Examination | Head, Eyes, Ears, Nose and Throat | 4 Participants |
| Total Participants | Number of Participants With Change in Physical Examination | Extremities/Joints | 1 Participants |
| Total Participants | Number of Participants With Change in Physical Examination | Heart | 0 Participants |
| Total Participants | Number of Participants With Change in Physical Examination | Skin | 2 Participants |
| Total Participants | Number of Participants With Change in Physical Examination | Lymph Nodes | 0 Participants |
| Total Participants | Number of Participants With Change in Physical Examination | Abdomen | 0 Participants |
| Total Participants | Number of Participants With Change in Physical Examination | General Appearance | 2 Participants |
| Total Participants | Number of Participants With Change in Physical Examination | Lungs | 0 Participants |
Primary
Number of Participants With Infusion-Associated Reactions (IARs)
IARs were defined as AEs that occurred during the infusion or within up to 24 hours after the start of infusion and were considered as related or possibly related to the study treatment by the investigator or the sponsor. Protocol-defined IAR: all AEs that were identified as an IAR by the investigator. Events occurring greater than or equal to (\>=) 24 hours after the start of an infusion might had been judged an IAR at the discretion of the investigator or sponsor.
Time frame: Within up to 24 hours after start of any infusion (during the treatment period i.e. from Baseline up to 64 weeks)
Population: Analysis was performed on safety population.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Olipudase Alfa: Adolescent Cohort | Number of Participants With Infusion-Associated Reactions (IARs) | 0 Participants |
| Olipudase Alfa: Child Cohort | Number of Participants With Infusion-Associated Reactions (IARs) | 6 Participants |
| Olipudase Alfa: Infant/Early Child Cohort | Number of Participants With Infusion-Associated Reactions (IARs) | 5 Participants |
| Total Participants | Number of Participants With Infusion-Associated Reactions (IARs) | 11 Participants |
Primary
Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Abnormalities
Criteria for potentially clinically significant ECG abnormalities: * High PR Interval: \>=180 milliseconds (ms) in adolescents, 170 ms in children, 160 ms in early children, and 140 ms in infants; * High QRS Interval: \>=110 ms in adolescents, 100 ms in children, 95 ms in early children and 85 ms in infants; * Prolonged QTc Fridericia (QTc F): \>450 ms in male adolescents, children, early children and infants or 470 ms in female adolescents, * QTc F \>500 ms; * QTc F increase from baseline \>60 ms.
Time frame: From Baseline up to End of Study (64 weeks)
Population: Analysis was performed on safety population.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Olipudase Alfa: Adolescent Cohort | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Abnormalities | Prolonged QTc F | 1 Participants |
| Olipudase Alfa: Adolescent Cohort | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Abnormalities | QTc F increase from baseline >60 ms | 0 Participants |
| Olipudase Alfa: Adolescent Cohort | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Abnormalities | QTc F >500 ms | 0 Participants |
| Olipudase Alfa: Adolescent Cohort | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Abnormalities | High QRS Duration | 0 Participants |
| Olipudase Alfa: Adolescent Cohort | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Abnormalities | High PR Duration | 2 Participants |
| Olipudase Alfa: Child Cohort | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Abnormalities | High QRS Duration | 0 Participants |
| Olipudase Alfa: Child Cohort | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Abnormalities | Prolonged QTc F | 1 Participants |
| Olipudase Alfa: Child Cohort | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Abnormalities | QTc F >500 ms | 0 Participants |
| Olipudase Alfa: Child Cohort | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Abnormalities | High PR Duration | 2 Participants |
| Olipudase Alfa: Child Cohort | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Abnormalities | QTc F increase from baseline >60 ms | 0 Participants |
| Olipudase Alfa: Infant/Early Child Cohort | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Abnormalities | High QRS Duration | 0 Participants |
| Olipudase Alfa: Infant/Early Child Cohort | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Abnormalities | High PR Duration | 2 Participants |
| Olipudase Alfa: Infant/Early Child Cohort | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Abnormalities | QTc F >500 ms | 0 Participants |
| Olipudase Alfa: Infant/Early Child Cohort | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Abnormalities | Prolonged QTc F | 0 Participants |
| Olipudase Alfa: Infant/Early Child Cohort | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Abnormalities | QTc F increase from baseline >60 ms | 0 Participants |
| Total Participants | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Abnormalities | Prolonged QTc F | 2 Participants |
| Total Participants | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Abnormalities | High PR Duration | 6 Participants |
| Total Participants | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Abnormalities | QTc F >500 ms | 0 Participants |
| Total Participants | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Abnormalities | High QRS Duration | 0 Participants |
| Total Participants | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Abnormalities | QTc F increase from baseline >60 ms | 0 Participants |
Primary
Number of Participants With Potentially Clinically Significant Vital Sign Abnormalities
* Heart Rate (HR) High: \>=120 beats per minute (bpm) (adolescents), \>=120 bpm (children), \>=140 bpm (early children), \>=175 bpm (infants) & increase from baseline (IFB) \>=20 bpm for all age categories. * HR Low: \<=50 bpm (adolescents), \<=50 bpm (children), \<=75 bpm (early children), \<=80 bpm (infants) & decrease from baseline (DFB) \>=20 bpm for all age categories. * Systolic BP (SBP) High: \>=119 mmHg (adolescents), 108 mmHg (children), 101 mmHg (in early children), 98 mmHg (infants) & IFB \>=20 mmHg for all age categories. * SBP Low: \<=90 mmHg (adolescents), \<= 80mm Hg (children), \<=70 mmHg (early children), \<=70 mmHg (infants) & DFB \>=20 mmHg for all age categories. * Diastolic BP (DBP) High:\>=78 mmHg (adolescents), \>=72 mmHg (children), \>=59 mmHg (in early children), \>=54 mmHg (infants) & IFB \>=10 mmHg for all age categories. * DBP Low:\<=54 mmHg (adolescents), \<=48 mmHg (children), \<=34 mmHg (early children), \<=34 mmHg (infants) & DFB \>=10 mmHg for all age categories.
Time frame: From Baseline up to End of Study (64 weeks)
Population: Analysis was performed on safety population. One participant may be counted in multiple (more than 1) categories.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Olipudase Alfa: Adolescent Cohort | Number of Participants With Potentially Clinically Significant Vital Sign Abnormalities | SBP High | 3 Participants |
| Olipudase Alfa: Adolescent Cohort | Number of Participants With Potentially Clinically Significant Vital Sign Abnormalities | Heart Rate High | 0 Participants |
| Olipudase Alfa: Adolescent Cohort | Number of Participants With Potentially Clinically Significant Vital Sign Abnormalities | DBP Low | 4 Participants |
| Olipudase Alfa: Adolescent Cohort | Number of Participants With Potentially Clinically Significant Vital Sign Abnormalities | DBP High | 4 Participants |
| Olipudase Alfa: Adolescent Cohort | Number of Participants With Potentially Clinically Significant Vital Sign Abnormalities | SBP Low | 2 Participants |
| Olipudase Alfa: Adolescent Cohort | Number of Participants With Potentially Clinically Significant Vital Sign Abnormalities | Heart Rate Low | 1 Participants |
| Olipudase Alfa: Child Cohort | Number of Participants With Potentially Clinically Significant Vital Sign Abnormalities | DBP Low | 9 Participants |
| Olipudase Alfa: Child Cohort | Number of Participants With Potentially Clinically Significant Vital Sign Abnormalities | DBP High | 8 Participants |
| Olipudase Alfa: Child Cohort | Number of Participants With Potentially Clinically Significant Vital Sign Abnormalities | SBP High | 6 Participants |
| Olipudase Alfa: Child Cohort | Number of Participants With Potentially Clinically Significant Vital Sign Abnormalities | Heart Rate Low | 0 Participants |
| Olipudase Alfa: Child Cohort | Number of Participants With Potentially Clinically Significant Vital Sign Abnormalities | Heart Rate High | 5 Participants |
| Olipudase Alfa: Child Cohort | Number of Participants With Potentially Clinically Significant Vital Sign Abnormalities | SBP Low | 5 Participants |
| Olipudase Alfa: Infant/Early Child Cohort | Number of Participants With Potentially Clinically Significant Vital Sign Abnormalities | Heart Rate High | 3 Participants |
| Olipudase Alfa: Infant/Early Child Cohort | Number of Participants With Potentially Clinically Significant Vital Sign Abnormalities | DBP High | 7 Participants |
| Olipudase Alfa: Infant/Early Child Cohort | Number of Participants With Potentially Clinically Significant Vital Sign Abnormalities | DBP Low | 2 Participants |
| Olipudase Alfa: Infant/Early Child Cohort | Number of Participants With Potentially Clinically Significant Vital Sign Abnormalities | SBP Low | 0 Participants |
| Olipudase Alfa: Infant/Early Child Cohort | Number of Participants With Potentially Clinically Significant Vital Sign Abnormalities | Heart Rate Low | 7 Participants |
| Olipudase Alfa: Infant/Early Child Cohort | Number of Participants With Potentially Clinically Significant Vital Sign Abnormalities | SBP High | 6 Participants |
| Total Participants | Number of Participants With Potentially Clinically Significant Vital Sign Abnormalities | DBP Low | 15 Participants |
| Total Participants | Number of Participants With Potentially Clinically Significant Vital Sign Abnormalities | SBP High | 15 Participants |
| Total Participants | Number of Participants With Potentially Clinically Significant Vital Sign Abnormalities | SBP Low | 7 Participants |
| Total Participants | Number of Participants With Potentially Clinically Significant Vital Sign Abnormalities | Heart Rate High | 8 Participants |
| Total Participants | Number of Participants With Potentially Clinically Significant Vital Sign Abnormalities | DBP High | 19 Participants |
| Total Participants | Number of Participants With Potentially Clinically Significant Vital Sign Abnormalities | Heart Rate Low | 8 Participants |
Primary
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
TEAEs were defined as adverse events (AEs) that occurred or worsened during the on-treatment period (time from the start of investigational medicinal product \[IMP\]) administration until end of study (i.e. up to 64 weeks).
Time frame: From Baseline up to End of study (64 weeks)
Population: Safety population included all participants who received at least 1 infusion (partial or total) of olipudase alfa.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Olipudase Alfa: Adolescent Cohort | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Any TEAEs | 4 Participants |
| Olipudase Alfa: Adolescent Cohort | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Any TEAEs leading to death | 0 Participants |
| Olipudase Alfa: Adolescent Cohort | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Any TEAEs leading to dose reduction | 0 Participants |
| Olipudase Alfa: Adolescent Cohort | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Any TEAEs potentially related to study drug | 2 Participants |
| Olipudase Alfa: Child Cohort | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Any TEAEs potentially related to study drug | 6 Participants |
| Olipudase Alfa: Child Cohort | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Any TEAEs leading to dose reduction | 4 Participants |
| Olipudase Alfa: Child Cohort | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Any TEAEs leading to death | 0 Participants |
| Olipudase Alfa: Child Cohort | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Any TEAEs | 9 Participants |
| Olipudase Alfa: Infant/Early Child Cohort | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Any TEAEs leading to dose reduction | 3 Participants |
| Olipudase Alfa: Infant/Early Child Cohort | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Any TEAEs potentially related to study drug | 5 Participants |
| Olipudase Alfa: Infant/Early Child Cohort | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Any TEAEs leading to death | 0 Participants |
| Olipudase Alfa: Infant/Early Child Cohort | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Any TEAEs | 7 Participants |
| Total Participants | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Any TEAEs potentially related to study drug | 13 Participants |
| Total Participants | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Any TEAEs | 20 Participants |
| Total Participants | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Any TEAEs leading to death | 0 Participants |
| Total Participants | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Any TEAEs leading to dose reduction | 7 Participants |
Primary
Number of Participants With Treatment-Emergent Antibody: Treatment-Induced/Treatment-Boosted Anti-drug Antibodies and Neutralizing Antibody (NAb)
Serum samples for immunogenicity assessment were analyzed to detect ADA. ADA response were categorized as: treatment emergent antibody i.e. treatment-induced/treatment-boosted response. A participant whose ADA status was positive anytime post-baseline and was negative or missing at baseline was considered to have treatment induced ADA. A participant whose ADA status was positive at baseline (pre-existing ADA) and the ADA titer level anytime post-baseline was significantly higher than that at baseline is considered to have treatment boosted ADA. Positive samples in the ADA assay were further analyzed in the NAb assay as positive NAb inhibition of catalytic activity and positive NAb inhibition of cellular uptake.
Time frame: From Baseline up to Week 64
Population: Analysis was performed on safety population.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Olipudase Alfa: Adolescent Cohort | Number of Participants With Treatment-Emergent Antibody: Treatment-Induced/Treatment-Boosted Anti-drug Antibodies and Neutralizing Antibody (NAb) | Positive NAb of catalytic activity | 0 Participants |
| Olipudase Alfa: Adolescent Cohort | Number of Participants With Treatment-Emergent Antibody: Treatment-Induced/Treatment-Boosted Anti-drug Antibodies and Neutralizing Antibody (NAb) | Treatment Induced ADA | 2 Participants |
| Olipudase Alfa: Adolescent Cohort | Number of Participants With Treatment-Emergent Antibody: Treatment-Induced/Treatment-Boosted Anti-drug Antibodies and Neutralizing Antibody (NAb) | Treatment boosted ADA | 0 Participants |
| Olipudase Alfa: Adolescent Cohort | Number of Participants With Treatment-Emergent Antibody: Treatment-Induced/Treatment-Boosted Anti-drug Antibodies and Neutralizing Antibody (NAb) | ADA positive since first dose of olipudase alfa | 2 Participants |
| Olipudase Alfa: Adolescent Cohort | Number of Participants With Treatment-Emergent Antibody: Treatment-Induced/Treatment-Boosted Anti-drug Antibodies and Neutralizing Antibody (NAb) | Positive NAb of cellular uptake | 0 Participants |
| Olipudase Alfa: Child Cohort | Number of Participants With Treatment-Emergent Antibody: Treatment-Induced/Treatment-Boosted Anti-drug Antibodies and Neutralizing Antibody (NAb) | ADA positive since first dose of olipudase alfa | 7 Participants |
| Olipudase Alfa: Child Cohort | Number of Participants With Treatment-Emergent Antibody: Treatment-Induced/Treatment-Boosted Anti-drug Antibodies and Neutralizing Antibody (NAb) | Positive NAb of catalytic activity | 1 Participants |
| Olipudase Alfa: Child Cohort | Number of Participants With Treatment-Emergent Antibody: Treatment-Induced/Treatment-Boosted Anti-drug Antibodies and Neutralizing Antibody (NAb) | Treatment boosted ADA | 1 Participants |
| Olipudase Alfa: Child Cohort | Number of Participants With Treatment-Emergent Antibody: Treatment-Induced/Treatment-Boosted Anti-drug Antibodies and Neutralizing Antibody (NAb) | Treatment Induced ADA | 6 Participants |
| Olipudase Alfa: Child Cohort | Number of Participants With Treatment-Emergent Antibody: Treatment-Induced/Treatment-Boosted Anti-drug Antibodies and Neutralizing Antibody (NAb) | Positive NAb of cellular uptake | 0 Participants |
| Olipudase Alfa: Infant/Early Child Cohort | Number of Participants With Treatment-Emergent Antibody: Treatment-Induced/Treatment-Boosted Anti-drug Antibodies and Neutralizing Antibody (NAb) | ADA positive since first dose of olipudase alfa | 3 Participants |
| Olipudase Alfa: Infant/Early Child Cohort | Number of Participants With Treatment-Emergent Antibody: Treatment-Induced/Treatment-Boosted Anti-drug Antibodies and Neutralizing Antibody (NAb) | Positive NAb of cellular uptake | 0 Participants |
| Olipudase Alfa: Infant/Early Child Cohort | Number of Participants With Treatment-Emergent Antibody: Treatment-Induced/Treatment-Boosted Anti-drug Antibodies and Neutralizing Antibody (NAb) | Treatment Induced ADA | 3 Participants |
| Olipudase Alfa: Infant/Early Child Cohort | Number of Participants With Treatment-Emergent Antibody: Treatment-Induced/Treatment-Boosted Anti-drug Antibodies and Neutralizing Antibody (NAb) | Positive NAb of catalytic activity | 0 Participants |
| Olipudase Alfa: Infant/Early Child Cohort | Number of Participants With Treatment-Emergent Antibody: Treatment-Induced/Treatment-Boosted Anti-drug Antibodies and Neutralizing Antibody (NAb) | Treatment boosted ADA | 0 Participants |
| Total Participants | Number of Participants With Treatment-Emergent Antibody: Treatment-Induced/Treatment-Boosted Anti-drug Antibodies and Neutralizing Antibody (NAb) | Positive NAb of catalytic activity | 1 Participants |
| Total Participants | Number of Participants With Treatment-Emergent Antibody: Treatment-Induced/Treatment-Boosted Anti-drug Antibodies and Neutralizing Antibody (NAb) | Treatment Induced ADA | 11 Participants |
| Total Participants | Number of Participants With Treatment-Emergent Antibody: Treatment-Induced/Treatment-Boosted Anti-drug Antibodies and Neutralizing Antibody (NAb) | Positive NAb of cellular uptake | 0 Participants |
| Total Participants | Number of Participants With Treatment-Emergent Antibody: Treatment-Induced/Treatment-Boosted Anti-drug Antibodies and Neutralizing Antibody (NAb) | ADA positive since first dose of olipudase alfa | 12 Participants |
| Total Participants | Number of Participants With Treatment-Emergent Antibody: Treatment-Induced/Treatment-Boosted Anti-drug Antibodies and Neutralizing Antibody (NAb) | Treatment boosted ADA | 1 Participants |
Secondary
Change From Baseline in Cycle Ergometry: Maximum Workload at Week 52
Cardiopulmonary status was assessed using a stationary one-wheeled cycle used as an ergometer to measure a person's work output under controlled conditions. Participants were asked to ride the cycle at increasing workload levels until they could no longer proceed. The workload at which participant stopped and cannot proceed was considered as maximum workload (in watt). As per the planned analysis, this assessment was not to be performed on participants that were \<=6 years of age or \<120 cm in height on day 1/week 0, therefore infant/early child cohort was not evaluable.
Time frame: Baseline, Week 52 (last assessment)
Population: Analysis was performed on mITT population. Here, overall number of participants analysed = participants with available data for this outcome measure. Data not collected in participants \<=6 years old, per protocol.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Olipudase Alfa: Adolescent Cohort | Change From Baseline in Cycle Ergometry: Maximum Workload at Week 52 | 38.3 watts | Standard Deviation 10.7 |
| Olipudase Alfa: Child Cohort | Change From Baseline in Cycle Ergometry: Maximum Workload at Week 52 | 20.5 watts | Standard Deviation 7.8 |
Secondary
Change From Baseline in Difference Between Actual Age and Bone Age of Participants at Week 52
Hand X-ray was performed on participant's left hand, fingers and wrist to assess bone age of participants. At each visit (Baseline and Week 52), difference between the bone age and actual age at that visit was calculated. Difference in age in months was calculated as bone age in months minus real age at time of assessment (in months) at specified time points. In this outcome measure change from baseline at Week 52 in the difference between actual age and bone age (in months) is reported.
Time frame: Baseline, Week 52 (last assessment)
Population: Analysis was performed on mITT population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Olipudase Alfa: Adolescent Cohort | Change From Baseline in Difference Between Actual Age and Bone Age of Participants at Week 52 | 1.595 months | Standard Deviation 3.114 |
| Olipudase Alfa: Child Cohort | Change From Baseline in Difference Between Actual Age and Bone Age of Participants at Week 52 | 2.876 months | Standard Deviation 14.048 |
| Olipudase Alfa: Infant/Early Child Cohort | Change From Baseline in Difference Between Actual Age and Bone Age of Participants at Week 52 | -0.702 months | Standard Deviation 9.573 |
| Total Participants | Change From Baseline in Difference Between Actual Age and Bone Age of Participants at Week 52 | 1.368 months | Standard Deviation 10.781 |
Secondary
Change From Baseline in Health Outcome Questionnaires : Pediatric Quality of Life (PedsQL) Generic Core Total Scale Scores at Week 52
PedsQL includes a child self-report (CS-R) for participants 5 to 18 years and parents' report (PR) of participants 2 to 18 years. CS-R: 23-item PedsQL Generic Core Scales report includes 4 scales, Physical (P), Emotional (E), Social (S), and School Functioning (SF). PR: 21-item PedsQL Generic Core Scales report includes P, E, S, and SF scales. Each item used a 5-point rating scale ( from 0=never to 4=almost always). Items are reverse scored and linearly transformed to a 0 (almost always) -100 (never) scale. Higher score indicates better Health Related Quality of Life (HRQoL). P, E, S and SF summary scores are calculated as mean of respective functioning items. Psychosocial Health Summary Score is calculated as mean of 13 or 15 items (E, S and SF). Generic core total scale score is calculated as the mean of all the 21 or 23 items (P, E, S and SF). All summary/total scores are mean of specific items and they all have values ranges from 0 to 100, where higher score=better HRQoL.
Time frame: Baseline, Week 52 (last assessment)
Population: Analysis performed on mITT population. Number of participants analyzed=participants with available data. PedsQL includes CS-R age 5 to18 (scoring categories 5 to 7, 8 to 12 and 13 to 18 years); PR age 2 to 18 (scoring categories 2 to 4, 5 to 7, 8 to 12 and 13 to 18 years). Since PedsQL scoring age categories are not the same as the age cohort defined for the study and since this is a single arm study, overall mITT population with available data is reported for this outcome.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Olipudase Alfa: Adolescent Cohort | Change From Baseline in Health Outcome Questionnaires : Pediatric Quality of Life (PedsQL) Generic Core Total Scale Scores at Week 52 | Social Functioning Scale:Parent Report | 11.7 score on a scale | Standard Deviation 19.8 |
| Olipudase Alfa: Adolescent Cohort | Change From Baseline in Health Outcome Questionnaires : Pediatric Quality of Life (PedsQL) Generic Core Total Scale Scores at Week 52 | Physical Functioning Scale: Child Report | 9.4 score on a scale | Standard Deviation 7.9 |
| Olipudase Alfa: Adolescent Cohort | Change From Baseline in Health Outcome Questionnaires : Pediatric Quality of Life (PedsQL) Generic Core Total Scale Scores at Week 52 | Emotional Functioning Scale: Child Report | 14.6 score on a scale | Standard Deviation 15.1 |
| Olipudase Alfa: Adolescent Cohort | Change From Baseline in Health Outcome Questionnaires : Pediatric Quality of Life (PedsQL) Generic Core Total Scale Scores at Week 52 | Social Functioning Scale: Child Report | 4.2 score on a scale | Standard Deviation 13.2 |
| Olipudase Alfa: Adolescent Cohort | Change From Baseline in Health Outcome Questionnaires : Pediatric Quality of Life (PedsQL) Generic Core Total Scale Scores at Week 52 | School Functioning Scale: Child Report | 2.1 score on a scale | Standard Deviation 12.6 |
| Olipudase Alfa: Adolescent Cohort | Change From Baseline in Health Outcome Questionnaires : Pediatric Quality of Life (PedsQL) Generic Core Total Scale Scores at Week 52 | Psychosocial Health Summary Score: Child Report | 6.8 score on a scale | Standard Deviation 8.3 |
| Olipudase Alfa: Adolescent Cohort | Change From Baseline in Health Outcome Questionnaires : Pediatric Quality of Life (PedsQL) Generic Core Total Scale Scores at Week 52 | Generic Core Total Scale Score : Child Report | 7.6 score on a scale | Standard Deviation 5.5 |
| Olipudase Alfa: Adolescent Cohort | Change From Baseline in Health Outcome Questionnaires : Pediatric Quality of Life (PedsQL) Generic Core Total Scale Scores at Week 52 | Physical Functioning Scale: Parent Report | 15.5 score on a scale | Standard Deviation 15.3 |
| Olipudase Alfa: Adolescent Cohort | Change From Baseline in Health Outcome Questionnaires : Pediatric Quality of Life (PedsQL) Generic Core Total Scale Scores at Week 52 | Emotional Functioning Scale: Parent Report | 12.2 score on a scale | Standard Deviation 22.9 |
| Olipudase Alfa: Adolescent Cohort | Change From Baseline in Health Outcome Questionnaires : Pediatric Quality of Life (PedsQL) Generic Core Total Scale Scores at Week 52 | School Functioning Scale: Parent Report | 1.0 score on a scale | Standard Deviation 20.5 |
| Olipudase Alfa: Adolescent Cohort | Change From Baseline in Health Outcome Questionnaires : Pediatric Quality of Life (PedsQL) Generic Core Total Scale Scores at Week 52 | Psychosocial Health Summary Score:Parent Report | 8.2 score on a scale | Standard Deviation 14.5 |
| Olipudase Alfa: Adolescent Cohort | Change From Baseline in Health Outcome Questionnaires : Pediatric Quality of Life (PedsQL) Generic Core Total Scale Scores at Week 52 | Generic Core Total Scale Score: Parent Report | 10.8 score on a scale | Standard Deviation 13.4 |
Secondary
Change From Baseline in Height Z-Scores at Week 52
Z-score for height of participants was evaluated. Height Z-Score, i.e., the height-for-age Z Score, is the number of standard deviations of the actual height of a child from the median height of the children of the corresponding age and sex as determined from the standard sample. A height Z-score of 0 is equal to the median and is considered normal. Negative numbers indicate values lower than the median and positive numbers indicate values higher than the median. For analysis, mean Z-score was calculated and an increase of mean height Z-score from baseline indicates an improvement on growth.
Time frame: Baseline, Week 52 (last assessment)
Population: Analysis was performed on mITT population. Here, overall number of participants analyzed = participants with available data for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Olipudase Alfa: Adolescent Cohort | Change From Baseline in Height Z-Scores at Week 52 | 0.606 Z-score | Standard Deviation 0.29 |
| Olipudase Alfa: Child Cohort | Change From Baseline in Height Z-Scores at Week 52 | 0.371 Z-score | Standard Deviation 0.344 |
| Olipudase Alfa: Infant/Early Child Cohort | Change From Baseline in Height Z-Scores at Week 52 | 0.736 Z-score | Standard Deviation 0.423 |
| Total Participants | Change From Baseline in Height Z-Scores at Week 52 | 0.555 Z-score | Standard Deviation 0.385 |
Secondary
Change From Baseline in Interstitial Lung Disease Score Measured Using High Resolution Computed Tomography (HRCT) at Week 52 For Both Lungs
Pulmonary imaging of chest using HRCT was obtained to quantitate the degree of possible infiltrative lung disease. Lung fields were assessed by a central reader & scored subjectively for the degree of interstitial lung disease on a scale ranges from 0 =normal, 1 =mild, 2=moderate and 3 =severe, where higher scores indicate more severity.
Time frame: Baseline, Week 52 (last assessment)
Population: Analysis was performed on mITT population. Here, overall number of participants analyzed = participants with available data for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Olipudase Alfa: Adolescent Cohort | Change From Baseline in Interstitial Lung Disease Score Measured Using High Resolution Computed Tomography (HRCT) at Week 52 For Both Lungs | -0.2188 score on a scale | Standard Deviation 1.002 |
| Olipudase Alfa: Child Cohort | Change From Baseline in Interstitial Lung Disease Score Measured Using High Resolution Computed Tomography (HRCT) at Week 52 For Both Lungs | -0.5833 score on a scale | Standard Deviation 0.7906 |
| Olipudase Alfa: Infant/Early Child Cohort | Change From Baseline in Interstitial Lung Disease Score Measured Using High Resolution Computed Tomography (HRCT) at Week 52 For Both Lungs | -0.8958 score on a scale | Standard Deviation 0.9982 |
| Total Participants | Change From Baseline in Interstitial Lung Disease Score Measured Using High Resolution Computed Tomography (HRCT) at Week 52 For Both Lungs | -0.6053 score on a scale | Standard Deviation 0.8851 |
Secondary
Percent Change From Baseline in Bone Biomarkers at Week 52
Bone biomarkers included bone specific alkaline phosphatase, C-Telopeptide.
Time frame: Baseline, Week 52
Population: Analysis was performed on mITT population. Here 'number analyzed' = participants with available data for specified category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Olipudase Alfa: Adolescent Cohort | Percent Change From Baseline in Bone Biomarkers at Week 52 | Alkaline phosphatase: Week 52 | -9.154 percent change | Standard Deviation 50.568 |
| Olipudase Alfa: Adolescent Cohort | Percent Change From Baseline in Bone Biomarkers at Week 52 | C-Telopeptide: Week 52 | 69.0 percent change | Standard Deviation 93.7 |
| Olipudase Alfa: Child Cohort | Percent Change From Baseline in Bone Biomarkers at Week 52 | C-Telopeptide: Week 52 | 92.5 percent change | Standard Deviation 78.4 |
| Olipudase Alfa: Child Cohort | Percent Change From Baseline in Bone Biomarkers at Week 52 | Alkaline phosphatase: Week 52 | 44.768 percent change | Standard Deviation 50.111 |
| Olipudase Alfa: Infant/Early Child Cohort | Percent Change From Baseline in Bone Biomarkers at Week 52 | Alkaline phosphatase: Week 52 | 35.040 percent change | Standard Deviation 61.983 |
| Olipudase Alfa: Infant/Early Child Cohort | Percent Change From Baseline in Bone Biomarkers at Week 52 | C-Telopeptide: Week 52 | 50.6 percent change | Standard Deviation 37 |
| Total Participants | Percent Change From Baseline in Bone Biomarkers at Week 52 | Alkaline phosphatase: Week 52 | 32.391 percent change | Standard Deviation 54.292 |
| Total Participants | Percent Change From Baseline in Bone Biomarkers at Week 52 | C-Telopeptide: Week 52 | 74.7 percent change | Standard Deviation 70.9 |
Secondary
Percent Change From Baseline in Efficacy Biomarkers Level at Week 52
Efficacy biomarkers included chitotriosidase, chemokine ligand 18 (CCL18), angiotensin-converting enzyme (ACE).
Time frame: Baseline, Week 52
Population: Analysis was performed on mITT population. Here 'number analyzed' = participants with available data for specified category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Olipudase Alfa: Adolescent Cohort | Percent Change From Baseline in Efficacy Biomarkers Level at Week 52 | Chitotriosidase at Week 52 | -55.8 percent change | Standard Deviation 21.1 |
| Olipudase Alfa: Adolescent Cohort | Percent Change From Baseline in Efficacy Biomarkers Level at Week 52 | ACE at Week 52 | -29.92 percent change | Standard Deviation 19.59 |
| Olipudase Alfa: Adolescent Cohort | Percent Change From Baseline in Efficacy Biomarkers Level at Week 52 | CCL18 at Week 52 | -55.25 percent change | Standard Deviation 13.23 |
| Olipudase Alfa: Child Cohort | Percent Change From Baseline in Efficacy Biomarkers Level at Week 52 | Chitotriosidase at Week 52 | -44.7 percent change | Standard Deviation 25 |
| Olipudase Alfa: Child Cohort | Percent Change From Baseline in Efficacy Biomarkers Level at Week 52 | ACE at Week 52 | -24.57 percent change | Standard Deviation 14.15 |
| Olipudase Alfa: Child Cohort | Percent Change From Baseline in Efficacy Biomarkers Level at Week 52 | CCL18 at Week 52 | -66.20 percent change | Standard Deviation 22.97 |
| Olipudase Alfa: Infant/Early Child Cohort | Percent Change From Baseline in Efficacy Biomarkers Level at Week 52 | CCL18 at Week 52 | -68.13 percent change | Standard Deviation 16.63 |
| Olipudase Alfa: Infant/Early Child Cohort | Percent Change From Baseline in Efficacy Biomarkers Level at Week 52 | Chitotriosidase at Week 52 | -74.6 percent change | Standard Deviation 18.1 |
| Olipudase Alfa: Infant/Early Child Cohort | Percent Change From Baseline in Efficacy Biomarkers Level at Week 52 | ACE at Week 52 | -29.64 percent change | Standard Deviation 17.8 |
| Total Participants | Percent Change From Baseline in Efficacy Biomarkers Level at Week 52 | Chitotriosidase at Week 52 | -58.0 percent change | Standard Deviation 24.8 |
| Total Participants | Percent Change From Baseline in Efficacy Biomarkers Level at Week 52 | ACE at Week 52 | -27.41 percent change | Standard Deviation 15.87 |
| Total Participants | Percent Change From Baseline in Efficacy Biomarkers Level at Week 52 | CCL18 at Week 52 | -64.68 percent change | Standard Deviation 19.01 |
Secondary
Percent Change From Baseline in Lipid Profile at Week 52
Lipid profile parameters included low density lipoprotein (LDL)-cholesterol, high density lipoprotein (HDL)-cholesterol and triglycerides.
Time frame: Baseline, Week 52
Population: Analysis was performed on mITT population. Here, 'number analyzed' = participants with available data for specified category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Olipudase Alfa: Adolescent Cohort | Percent Change From Baseline in Lipid Profile at Week 52 | Triglycerides at Week 52 | -56.28 percent change | Standard Deviation 5.95 |
| Olipudase Alfa: Adolescent Cohort | Percent Change From Baseline in Lipid Profile at Week 52 | LDL Cholesterol at Week 52 | -38.31 percent change | Standard Deviation 7.44 |
| Olipudase Alfa: Adolescent Cohort | Percent Change From Baseline in Lipid Profile at Week 52 | HDL Cholesterol at Week 52 | 118.63 percent change | Standard Deviation 66.75 |
| Olipudase Alfa: Child Cohort | Percent Change From Baseline in Lipid Profile at Week 52 | LDL Cholesterol at Week 52 | -35.82 percent change | Standard Deviation 23 |
| Olipudase Alfa: Child Cohort | Percent Change From Baseline in Lipid Profile at Week 52 | Triglycerides at Week 52 | -47.45 percent change | Standard Deviation 18.08 |
| Olipudase Alfa: Child Cohort | Percent Change From Baseline in Lipid Profile at Week 52 | HDL Cholesterol at Week 52 | 87.49 percent change | Standard Deviation 52.89 |
| Olipudase Alfa: Infant/Early Child Cohort | Percent Change From Baseline in Lipid Profile at Week 52 | HDL Cholesterol at Week 52 | 124.74 percent change | Standard Deviation 84.57 |
| Olipudase Alfa: Infant/Early Child Cohort | Percent Change From Baseline in Lipid Profile at Week 52 | LDL Cholesterol at Week 52 | -34.04 percent change | Standard Deviation 16.69 |
| Olipudase Alfa: Infant/Early Child Cohort | Percent Change From Baseline in Lipid Profile at Week 52 | Triglycerides at Week 52 | -56.44 percent change | Standard Deviation 25.01 |
| Total Participants | Percent Change From Baseline in Lipid Profile at Week 52 | LDL Cholesterol at Week 52 | -35.78 percent change | Standard Deviation 18 |
| Total Participants | Percent Change From Baseline in Lipid Profile at Week 52 | Triglycerides at Week 52 | -52.37 percent change | Standard Deviation 19.02 |
| Total Participants | Percent Change From Baseline in Lipid Profile at Week 52 | HDL Cholesterol at Week 52 | 106.76 percent change | Standard Deviation 66.82 |
Secondary
Percent Change From Baseline in Percent Predicted Hemoglobin-Adjusted Diffusing Capacity of Carbon Monoxide (DLco) at Week 52
Percent predicted Hemoglobin-adjusted DLco was calculated as: 100\*Adjusted DLco/Predicted DLco in unit of mL CO/min/mmHg where, adjusted DLco = Observed DLco (in mL CO/min/mmHg) divided by Hemoglobin-adjusted factor. Per planned analysis, pulmonary function testing (PFT) was to be performed only on participants \>=5 years of age therefore, data for participants in age cohort: infant/early child were not collected.
Time frame: Baseline, Week 52 (last assessment)
Population: Analysis was performed on mITT population. Here, overall number of participants analyzed = participants with available data for this outcome measure. PFT was to be performed only on participants \>=5 years of age and who could perform the test, therefore, for participants in age cohort: infant/early child data were not collected.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Olipudase Alfa: Adolescent Cohort | Percent Change From Baseline in Percent Predicted Hemoglobin-Adjusted Diffusing Capacity of Carbon Monoxide (DLco) at Week 52 | 28.01 percent change | Standard Deviation 16.22 |
| Olipudase Alfa: Child Cohort | Percent Change From Baseline in Percent Predicted Hemoglobin-Adjusted Diffusing Capacity of Carbon Monoxide (DLco) at Week 52 | 35.41 percent change | Standard Deviation 35.08 |
Secondary
Percent Change From Baseline in Pharmacodynamic Biomarkers: Plasma Sphingomyelin and Lyso-Sphingomyelin Levels at Week 52
Sphingomyelin and Lyso-sphingomyelin levels were assessed in plasma. Lyso-sphingomyelin is a metabolite of sphingomyelin.
Time frame: Baseline, Week 52 (Pre- infusion)
Population: Analysis was performed on PD population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Olipudase Alfa: Adolescent Cohort | Percent Change From Baseline in Pharmacodynamic Biomarkers: Plasma Sphingomyelin and Lyso-Sphingomyelin Levels at Week 52 | Sphingomyelin: Pre-infusion at Week 52 | -4.4 percent change | Standard Deviation 24.6 |
| Olipudase Alfa: Adolescent Cohort | Percent Change From Baseline in Pharmacodynamic Biomarkers: Plasma Sphingomyelin and Lyso-Sphingomyelin Levels at Week 52 | Lyso-Sphingomyelin: Pre-infusion at Week 52 | -84.050 percent change | Standard Deviation 5.249 |
| Olipudase Alfa: Child Cohort | Percent Change From Baseline in Pharmacodynamic Biomarkers: Plasma Sphingomyelin and Lyso-Sphingomyelin Levels at Week 52 | Lyso-Sphingomyelin: Pre-infusion at Week 52 | -88.029 percent change | Standard Deviation 8.156 |
| Olipudase Alfa: Child Cohort | Percent Change From Baseline in Pharmacodynamic Biomarkers: Plasma Sphingomyelin and Lyso-Sphingomyelin Levels at Week 52 | Sphingomyelin: Pre-infusion at Week 52 | -37.1 percent change | Standard Deviation 24.2 |
| Olipudase Alfa: Infant/Early Child Cohort | Percent Change From Baseline in Pharmacodynamic Biomarkers: Plasma Sphingomyelin and Lyso-Sphingomyelin Levels at Week 52 | Sphingomyelin: Pre-infusion at Week 52 | -18.6 percent change | Standard Deviation 40.3 |
| Olipudase Alfa: Infant/Early Child Cohort | Percent Change From Baseline in Pharmacodynamic Biomarkers: Plasma Sphingomyelin and Lyso-Sphingomyelin Levels at Week 52 | Lyso-Sphingomyelin: Pre-infusion at Week 52 | -87.951 percent change | Standard Deviation 1.775 |
| Total Participants | Percent Change From Baseline in Pharmacodynamic Biomarkers: Plasma Sphingomyelin and Lyso-Sphingomyelin Levels at Week 52 | Sphingomyelin: Pre-infusion at Week 52 | -24.1 percent change | Standard Deviation 32 |
| Total Participants | Percent Change From Baseline in Pharmacodynamic Biomarkers: Plasma Sphingomyelin and Lyso-Sphingomyelin Levels at Week 52 | Lyso-Sphingomyelin: Pre-infusion at Week 52 | -87.206 percent change | Standard Deviation 5.998 |
Secondary
Percent Change From Baseline in Spleen Volume and Liver Volume at Week 52
Spleen and liver volumes was assessed by abdominal magnetic resonance imaging (MRI).
Time frame: Baseline, Week 52 (last assessment)
Population: Analysis was performed on modified intent-to-treat (mITT) population which included all participants who were exposed to IMP, regardless of the amount of treatment administered (partial or total).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Olipudase Alfa: Adolescent Cohort | Percent Change From Baseline in Spleen Volume and Liver Volume at Week 52 | Change in spleen volume | -46.936 percent change | Standard Deviation 3.041 |
| Olipudase Alfa: Adolescent Cohort | Percent Change From Baseline in Spleen Volume and Liver Volume at Week 52 | Change in liver volume | -41.726 percent change | Standard Deviation 6.13 |
| Olipudase Alfa: Child Cohort | Percent Change From Baseline in Spleen Volume and Liver Volume at Week 52 | Change in liver volume | -36.741 percent change | Standard Deviation 10.469 |
| Olipudase Alfa: Child Cohort | Percent Change From Baseline in Spleen Volume and Liver Volume at Week 52 | Change in spleen volume | -46.038 percent change | Standard Deviation 11.767 |
| Olipudase Alfa: Infant/Early Child Cohort | Percent Change From Baseline in Spleen Volume and Liver Volume at Week 52 | Change in spleen volume | -54.590 percent change | Standard Deviation 7.562 |
| Olipudase Alfa: Infant/Early Child Cohort | Percent Change From Baseline in Spleen Volume and Liver Volume at Week 52 | Change in liver volume | -45.060 percent change | Standard Deviation 8.203 |
| Total Participants | Percent Change From Baseline in Spleen Volume and Liver Volume at Week 52 | Change in spleen volume | -49.211 percent change | Standard Deviation 9.713 |
| Total Participants | Percent Change From Baseline in Spleen Volume and Liver Volume at Week 52 | Change in liver volume | -40.560 percent change | Standard Deviation 9.37 |
Secondary
Pharmacokinetic Parameter: AUC0-last, AUC(0-tau) of Olipudase Alfa
AUClast: Area under the plasma concentration versus time curve calculated using the trapezoidal method from time zero to the time of last measured concentration. AUC(0-tau): area under the plot of the drug concentration versus the time curve from time 0 to the end of the dosing interval (tau), where dosing interval was 2 weeks.
Time frame: Adolescent: at pre-infusion, EOI, 2 h, 6 h, 24 h, 48 h & 72 h (at first 3.0 mg/kg dose) or 96 h (at Week 52) post EOI; Child & infant/early child: pre-infusion, 0-30 min, 2-4 h, 6-12 h, 24-36 h, and 84-96 h post EOI at the first 3.0 mg/kg dose & Week 52
Population: Analysis was performed on PK population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Olipudase Alfa: Adolescent Cohort | Pharmacokinetic Parameter: AUC0-last, AUC(0-tau) of Olipudase Alfa | AUClast: at 3.0 mg/kg First dose | 452 μg*h/mL | Standard Deviation 49.7 |
| Olipudase Alfa: Adolescent Cohort | Pharmacokinetic Parameter: AUC0-last, AUC(0-tau) of Olipudase Alfa | AUClast: at 3.0 mg/kg at Week 52 | 461 μg*h/mL | Standard Deviation 28.1 |
| Olipudase Alfa: Adolescent Cohort | Pharmacokinetic Parameter: AUC0-last, AUC(0-tau) of Olipudase Alfa | AUC(0-τ): at 3.0 mg/kg First dose | 478 μg*h/mL | Standard Deviation 55.4 |
| Olipudase Alfa: Adolescent Cohort | Pharmacokinetic Parameter: AUC0-last, AUC(0-tau) of Olipudase Alfa | AUC(0-τ): at 3.0 mg/kg at Week 52 | 489 μg*h/mL | Standard Deviation 32.7 |
| Olipudase Alfa: Child Cohort | Pharmacokinetic Parameter: AUC0-last, AUC(0-tau) of Olipudase Alfa | AUC(0-τ): at 3.0 mg/kg at Week 52 | 508 μg*h/mL | Standard Deviation 108 |
| Olipudase Alfa: Child Cohort | Pharmacokinetic Parameter: AUC0-last, AUC(0-tau) of Olipudase Alfa | AUClast: at 3.0 mg/kg First dose | 441 μg*h/mL | Standard Deviation 97.8 |
| Olipudase Alfa: Child Cohort | Pharmacokinetic Parameter: AUC0-last, AUC(0-tau) of Olipudase Alfa | AUC(0-τ): at 3.0 mg/kg First dose | 465 μg*h/mL | Standard Deviation 102 |
| Olipudase Alfa: Child Cohort | Pharmacokinetic Parameter: AUC0-last, AUC(0-tau) of Olipudase Alfa | AUClast: at 3.0 mg/kg at Week 52 | 482 μg*h/mL | Standard Deviation 101 |
| Olipudase Alfa: Infant/Early Child Cohort | Pharmacokinetic Parameter: AUC0-last, AUC(0-tau) of Olipudase Alfa | AUC(0-τ): at 3.0 mg/kg at Week 52 | 451 μg*h/mL | Standard Deviation 68.2 |
| Olipudase Alfa: Infant/Early Child Cohort | Pharmacokinetic Parameter: AUC0-last, AUC(0-tau) of Olipudase Alfa | AUClast: at 3.0 mg/kg at Week 52 | 429 μg*h/mL | Standard Deviation 62.6 |
| Olipudase Alfa: Infant/Early Child Cohort | Pharmacokinetic Parameter: AUC0-last, AUC(0-tau) of Olipudase Alfa | AUC(0-τ): at 3.0 mg/kg First dose | 432 μg*h/mL | Standard Deviation 93 |
| Olipudase Alfa: Infant/Early Child Cohort | Pharmacokinetic Parameter: AUC0-last, AUC(0-tau) of Olipudase Alfa | AUClast: at 3.0 mg/kg First dose | 412 μg*h/mL | Standard Deviation 87.4 |
Secondary
Pharmacokinetic Parameter: Maximum Observed Plasma Concentration (Cmax) of Olipudase Alfa
Cmax: maximum plasma concentration observed.
Time frame: Adolescent: at pre-infusion, EOI, 2 h, 6 h, 24 h, 48 h & 72 h (at first 3.0 mg/kg dose) or 96 h (at Week 52) post EOI; Child & infant/early child: pre-infusion, 0-30 min, 2-4 h, 6-12 h, 24-36 h, and 84-96 h post EOI at the first 3.0 mg/kg dose & Week 52
Population: Analysis was performed on PK population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Olipudase Alfa: Adolescent Cohort | Pharmacokinetic Parameter: Maximum Observed Plasma Concentration (Cmax) of Olipudase Alfa | 3.0 mg/kg at Week 52 | 22.4 μg/mL | Standard Deviation 1.02 |
| Olipudase Alfa: Adolescent Cohort | Pharmacokinetic Parameter: Maximum Observed Plasma Concentration (Cmax) of Olipudase Alfa | 3.0 mg/kg at First dose | 28.0 μg/mL | Standard Deviation 4.88 |
| Olipudase Alfa: Child Cohort | Pharmacokinetic Parameter: Maximum Observed Plasma Concentration (Cmax) of Olipudase Alfa | 3.0 mg/kg at Week 52 | 24.4 μg/mL | Standard Deviation 7.51 |
| Olipudase Alfa: Child Cohort | Pharmacokinetic Parameter: Maximum Observed Plasma Concentration (Cmax) of Olipudase Alfa | 3.0 mg/kg at First dose | 23.0 μg/mL | Standard Deviation 3.93 |
| Olipudase Alfa: Infant/Early Child Cohort | Pharmacokinetic Parameter: Maximum Observed Plasma Concentration (Cmax) of Olipudase Alfa | 3.0 mg/kg at First dose | 22.1 μg/mL | Standard Deviation 7.19 |
| Olipudase Alfa: Infant/Early Child Cohort | Pharmacokinetic Parameter: Maximum Observed Plasma Concentration (Cmax) of Olipudase Alfa | 3.0 mg/kg at Week 52 | 22.4 μg/mL | Standard Deviation 4.18 |
Secondary
Pharmacokinetic Parameter: Terminal Half-Life of Olipudase Alfa
Half-life is the time measured for the plasma concentration of drug to decrease by one half.
Time frame: Adolescent: at pre-infusion, EOI, 2 h, 6 h, 24 h, 48 h & 72 h (at first 3.0 mg/kg dose) or 96 h (at Week 52) post EOI; Child & infant/early child: pre-infusion, 0-30 min, 2-4 h, 6-12 h, 24-36 h, and 84-96 h post EOI at the first 3.0 mg/kg dose & Week 52
Population: Analysis was performed on PK population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Olipudase Alfa: Adolescent Cohort | Pharmacokinetic Parameter: Terminal Half-Life of Olipudase Alfa | 3.0 mg/kg at First dose | 17.1 hours (h) | Standard Deviation 1.15 |
| Olipudase Alfa: Adolescent Cohort | Pharmacokinetic Parameter: Terminal Half-Life of Olipudase Alfa | 3.0 mg/kg at Week 52 | 24.3 hours (h) | Standard Deviation 2.88 |
| Olipudase Alfa: Child Cohort | Pharmacokinetic Parameter: Terminal Half-Life of Olipudase Alfa | 3.0 mg/kg at First dose | 23.1 hours (h) | Standard Deviation 2.11 |
| Olipudase Alfa: Child Cohort | Pharmacokinetic Parameter: Terminal Half-Life of Olipudase Alfa | 3.0 mg/kg at Week 52 | 23.3 hours (h) | Standard Deviation 1.42 |
| Olipudase Alfa: Infant/Early Child Cohort | Pharmacokinetic Parameter: Terminal Half-Life of Olipudase Alfa | 3.0 mg/kg at First dose | 22.6 hours (h) | Standard Deviation 1.25 |
| Olipudase Alfa: Infant/Early Child Cohort | Pharmacokinetic Parameter: Terminal Half-Life of Olipudase Alfa | 3.0 mg/kg at Week 52 | 23.6 hours (h) | Standard Deviation 1.35 |
Secondary
Pharmacokinetic Parameter: Time to Reach Cmax (Tmax) of Olipudase Alfa
tmax: time to reach maximum plasma concentration observed.
Time frame: Adolescent: at pre-infusion, EOI, 2 h, 6 h, 24 h, 48 h & 72 h (at first 3.0 mg/kg dose) or 96 h (at Week 52) post EOI; Child & infant/early child: pre-infusion, 0-30 min, 2-4 h, 6-12 h, 24-36 h, and 84-96 h post EOI at the first 3.0 mg/kg dose & Week 52
Population: Analysis was performed on PK population.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Olipudase Alfa: Adolescent Cohort | Pharmacokinetic Parameter: Time to Reach Cmax (Tmax) of Olipudase Alfa | 3.0 mg/kg at First dose | 3.94 hours (h) |
| Olipudase Alfa: Adolescent Cohort | Pharmacokinetic Parameter: Time to Reach Cmax (Tmax) of Olipudase Alfa | 3.0 mg/kg at Week 52 | 3.81 hours (h) |
| Olipudase Alfa: Child Cohort | Pharmacokinetic Parameter: Time to Reach Cmax (Tmax) of Olipudase Alfa | 3.0 mg/kg at First dose | 4.00 hours (h) |
| Olipudase Alfa: Child Cohort | Pharmacokinetic Parameter: Time to Reach Cmax (Tmax) of Olipudase Alfa | 3.0 mg/kg at Week 52 | 4.25 hours (h) |
| Olipudase Alfa: Infant/Early Child Cohort | Pharmacokinetic Parameter: Time to Reach Cmax (Tmax) of Olipudase Alfa | 3.0 mg/kg at Week 52 | 4.42 hours (h) |
| Olipudase Alfa: Infant/Early Child Cohort | Pharmacokinetic Parameter: Time to Reach Cmax (Tmax) of Olipudase Alfa | 3.0 mg/kg at First dose | 4.13 hours (h) |
Secondary
Pharmacokinetic Parameter: Total Body Clearance (CL) of Olipudase Alfa
Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. Total body clearance of a drug from the plasma calculated using equations below: CL = Dose / AUC after the first dose.
Time frame: Adolescent: at pre-infusion, EOI, 2 h, 6 h, 24 h, 48 h & 72 h (at first 3.0 mg/kg dose) or 96 h (at Week 52) post EOI; Child & infant/early child: pre-infusion, 0-30 min, 2-4 h, 6-12 h, 24-36 h, and 84-96 h post EOI at the first 3.0 mg/kg dose & Week 52
Population: Analysis was performed on PK population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Olipudase Alfa: Adolescent Cohort | Pharmacokinetic Parameter: Total Body Clearance (CL) of Olipudase Alfa | 3.0 mg/kg at Week 52 | 6.16 milliliter/hour/kilograms (mL/h/kg) | Standard Deviation 0.411 |
| Olipudase Alfa: Adolescent Cohort | Pharmacokinetic Parameter: Total Body Clearance (CL) of Olipudase Alfa | 3.0 mg/kg at First dose | 6.34 milliliter/hour/kilograms (mL/h/kg) | Standard Deviation 0.741 |
| Olipudase Alfa: Child Cohort | Pharmacokinetic Parameter: Total Body Clearance (CL) of Olipudase Alfa | 3.0 mg/kg at Week 52 | 6.16 milliliter/hour/kilograms (mL/h/kg) | Standard Deviation 1.38 |
| Olipudase Alfa: Child Cohort | Pharmacokinetic Parameter: Total Body Clearance (CL) of Olipudase Alfa | 3.0 mg/kg at First dose | 6.75 milliliter/hour/kilograms (mL/h/kg) | Standard Deviation 1.57 |
| Olipudase Alfa: Infant/Early Child Cohort | Pharmacokinetic Parameter: Total Body Clearance (CL) of Olipudase Alfa | 3.0 mg/kg at First dose | 7.20 milliliter/hour/kilograms (mL/h/kg) | Standard Deviation 1.4 |
| Olipudase Alfa: Infant/Early Child Cohort | Pharmacokinetic Parameter: Total Body Clearance (CL) of Olipudase Alfa | 3.0 mg/kg at Week 52 | 6.79 milliliter/hour/kilograms (mL/h/kg) | Standard Deviation 1.08 |
Secondary
Pharmacokinetic Parameter: Volume of Distribution at Steady State (Vss) of Olipudase Alfa
Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug.
Time frame: Adolescent: at pre-infusion, EOI, 2 h, 6 h, 24 h, 48 h & 72 h (at first 3.0 mg/kg dose) or 96 h (at Week 52) post EOI; Child & infant/early child: pre-infusion, 0-30 min, 2-4 h, 6-12 h, 24-36 h, and 84-96 h post EOI at the first 3.0 mg/kg dose & Week 52
Population: Analysis was performed on PK population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Olipudase Alfa: Adolescent Cohort | Pharmacokinetic Parameter: Volume of Distribution at Steady State (Vss) of Olipudase Alfa | 3.0 mg/kg at First dose | 133 milliliter per kilogram (mL/kg) | Standard Deviation 13.5 |
| Olipudase Alfa: Adolescent Cohort | Pharmacokinetic Parameter: Volume of Distribution at Steady State (Vss) of Olipudase Alfa | 3.0 mg/kg at Week 52 | 172 milliliter per kilogram (mL/kg) | Standard Deviation 11.6 |
| Olipudase Alfa: Child Cohort | Pharmacokinetic Parameter: Volume of Distribution at Steady State (Vss) of Olipudase Alfa | 3.0 mg/kg at First dose | 166 milliliter per kilogram (mL/kg) | Standard Deviation 39.1 |
| Olipudase Alfa: Child Cohort | Pharmacokinetic Parameter: Volume of Distribution at Steady State (Vss) of Olipudase Alfa | 3.0 mg/kg at Week 52 | 153 milliliter per kilogram (mL/kg) | Standard Deviation 32.7 |
| Olipudase Alfa: Infant/Early Child Cohort | Pharmacokinetic Parameter: Volume of Distribution at Steady State (Vss) of Olipudase Alfa | 3.0 mg/kg at First dose | 165 milliliter per kilogram (mL/kg) | Standard Deviation 31 |
| Olipudase Alfa: Infant/Early Child Cohort | Pharmacokinetic Parameter: Volume of Distribution at Steady State (Vss) of Olipudase Alfa | 3.0 mg/kg at Week 52 | 161 milliliter per kilogram (mL/kg) | Standard Deviation 20.9 |
Secondary
Pharmacokinetic (PK) Parameter: Plasma Concentration of Olipudase Alfa at the End of Infusion (Ceoi)
Ceoi was defined as the plasma concentration at the end of infusion (EOI). Data collected for child and Infant/child age groups at 0-30 min from end of infusion was considered at end of infusion.
Time frame: At the end of infusion of the first 3.0 mg/kg dose and at Week 52
Population: Analysis was performed on PK population which included all participants who received at least 1 infusion of study medication and had evaluable PK data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Olipudase Alfa: Adolescent Cohort | Pharmacokinetic (PK) Parameter: Plasma Concentration of Olipudase Alfa at the End of Infusion (Ceoi) | 3.0 mg/kg at First dose | 28.0 micrograms per milliliter (μg/mL) | Standard Deviation 4.88 |
| Olipudase Alfa: Adolescent Cohort | Pharmacokinetic (PK) Parameter: Plasma Concentration of Olipudase Alfa at the End of Infusion (Ceoi) | 3.0 mg/kg at Day 52 | 22.4 micrograms per milliliter (μg/mL) | Standard Deviation 1.02 |
| Olipudase Alfa: Child Cohort | Pharmacokinetic (PK) Parameter: Plasma Concentration of Olipudase Alfa at the End of Infusion (Ceoi) | 3.0 mg/kg at First dose | 23.0 micrograms per milliliter (μg/mL) | Standard Deviation 3.93 |
| Olipudase Alfa: Child Cohort | Pharmacokinetic (PK) Parameter: Plasma Concentration of Olipudase Alfa at the End of Infusion (Ceoi) | 3.0 mg/kg at Day 52 | 24.4 micrograms per milliliter (μg/mL) | Standard Deviation 7.51 |
| Olipudase Alfa: Infant/Early Child Cohort | Pharmacokinetic (PK) Parameter: Plasma Concentration of Olipudase Alfa at the End of Infusion (Ceoi) | 3.0 mg/kg at First dose | 22.1 micrograms per milliliter (μg/mL) | Standard Deviation 7.19 |
| Olipudase Alfa: Infant/Early Child Cohort | Pharmacokinetic (PK) Parameter: Plasma Concentration of Olipudase Alfa at the End of Infusion (Ceoi) | 3.0 mg/kg at Day 52 | 22.4 micrograms per milliliter (μg/mL) | Standard Deviation 4.18 |
Secondary
Physician's Global Assessment of Participant's Progress: Observed Scores at Week 52
Physician assessed participant's current clinical status (refers to clinical status at Week 52 in comparison to Baseline) was evaluated by marking 1 of the following 7 categories: • marked improvement, • moderate improvement, • mild improvement, • no change, • mild worsening, • moderate worsening, or • marked worsening. These 7 categories were converted to scores as follows: 3 = marked improvement of daily activities, 2 = moderate improvement of daily activities, 1 = mild improvement of daily activities, 0 = no change, -1 = mild worsening of daily activities, -2 = moderate worsening of daily activities, -3 = marked worsening of daily activities where higher score indicated improvement in daily activities as compared to baseline. In this outcome measure, observed scores of participant's clinical status at Week 52 are reported.
Time frame: Week 52 (last assessment)
Population: Analysis was performed on mITT population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Olipudase Alfa: Adolescent Cohort | Physician's Global Assessment of Participant's Progress: Observed Scores at Week 52 | 1.3 score on a scale | Standard Deviation 1.5 |
| Olipudase Alfa: Child Cohort | Physician's Global Assessment of Participant's Progress: Observed Scores at Week 52 | 2.4 score on a scale | Standard Deviation 1 |
| Olipudase Alfa: Infant/Early Child Cohort | Physician's Global Assessment of Participant's Progress: Observed Scores at Week 52 | 2.7 score on a scale | Standard Deviation 0.8 |
| Total Participants | Physician's Global Assessment of Participant's Progress: Observed Scores at Week 52 | 2.3 score on a scale | Standard Deviation 1.1 |